Compounds and compositions for inducing chondrogenesis

ABSTRACT

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds; and methods of using such compounds for treating joint damage or injury in a mammal, for inducing hyaline cartilage production or for inducing differentiation of chondrogenic progenitor cells into mature chondrocytes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/620,407 filed 6 Dec. 2019, which is a 371 U.S. national phaseapplication of international application number PCT/IB2018/054123, filed7 Jun. 2018, which claims the benefit of U.S. provisional applicationSer. No. 62/517,394 filed 9 Jun. 2017; each of which is incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for treatingor preventing joint damage resulting from joint injury and arthritis.

BACKGROUND OF THE INVENTION

Osteoarthritis (OA) represents the most common musculoskeletal disorder.Approximately 40 million Americans are currently affected and thisnumber is predicted to increase to 60 million within the next twentyyears as a result of the aging population and an increase in lifeexpectancy, making it the fourth leading cause of disability. OA ischaracterized by a slow degenerative breakdown of the joint includingboth the articular cartilage (containing the cells and matrix whichproduce lubrication and cushioning for the joint) and the subchondralbone underlying the articular cartilage. OA can be considered aconsequence of various etiologic factors. For example, it can be causedby abnormal biomechanical stress or genetic or acquired abnormalities ofarticular cartilage or bone. Current OA therapies include pain reliefwith oral NSAIDs or selective cyclooxygenase 2 (COX-2) inhibitors,intra-articular (IA) injection with agents such as corticorsteroids andhyaluronan, and surgical approaches.

Joint damage, e.g., acute joint injury, such as a meniscal or ligamenttear, or an intra-articular fracture can also lead to arthritis, e.g.,posttraumatic arthritis. Because articular cartilage has a limitedability to repair, even small undetectable damage can often get worseover time and lead to OA. Current treatments for joint injury caninclude surgery and other invasive procedures focused on regeneration ofdamaged joints as well as treatment with agents to reduce pain andinflammation.

Mesenchymal stem cells (MSCs) are present in adult articular cartilageand upon isolation can be programmed in vitro to undergo differentiationto chondrocytes and other mesenchymal cell lineages, and may be used forcartilage regeneration. In part, the process is regulated by growthfactors (TGFβs, BMPs), serum conditions and cell-cell contact.

WO2011/008773 describes peptide compositions and use of thosecompositions for treating or preventing arthritis and joint injury andfor inducing differentiation of mesenchymal cells into chondrocytes.Additionally, WO2012/129562 describes small molecule compounds,compositions and use of those compositions for amelioration of arthritisand joint injury and for inducing differentiation of mesenchymal cellsinto chondrocytes.

Though surgical techniques, and regenerative technology have made someprogress in restoration of cartilage, slowing degeneration, and improvedrepair of joint damage, a continued need exists for improvement ofcompositions and methods for effective cartilage regeneration, treatmentof joint damage and amelioration or prevention of OA.

SUMMARY OF THE INVENTION

The present invention relates to compositions and methods for treatingor preventing joint damage resulting from joint injury and arthritis.

In one aspect, the invention provides a compound of Formula (I), or apharmaceutically acceptable salt, or stereoisomer thereof;

-   -   wherein R⁰ is hydrogen or C₁₋₆alkyl;    -   R² is phenyl; a 5- or 6-membered heteroaryl or a 5- or        6-membered heterocyclyl, each having 1 to 3 heteroatoms selected        from N, O and S; wherein R² is unsubstituted or substituted;    -   R³ is a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms        selected from N, O and S; wherein R³ is unsubstituted or        substituted,    -   R^(1a), R^(1b), R^(4a), and R^(4b) are each independently        hydrogen, halo, hydroxyl, C₁₋₆alkoxy, C₁₋₆alkyl, —NR⁷R⁸ or        —NR⁷—(CR⁹R¹⁰)₂₋₄—OR¹¹; or wherein one of R^(1a) and R^(1b)        together with one of R^(4a) and R^(4b) form a cyclopropyl with        the two carbon atoms to which said R^(1a), R^(1b), R^(4a) and        R^(4b) are respectively attached;    -   R⁵, R⁶, R⁷, R⁹, R¹⁰ and R¹¹ are each independently hydrogen or        C₁₋₆alkyl;    -   R⁸ is hydrogen, C₃₋₇ cycloalkyl or a 5- or 6-membered        heterocyclyl having 1-3 heteroatoms selected from N, O and S;        wherein said C₃₋₇ cycloalkyl or 5- or 6-membered heterocyclyl of        R⁸ is unsubstituted or substituted;    -   alternatively, R⁵ and R⁶ or R⁷ and R⁸ together with the nitrogen        atom to which they are attached in —NR⁵R⁶ or —NR⁷R⁸ respectively        form a 5- or 6-membered heterocyclyl having 1-3 heteroatoms        selected from N, O and S;    -   provided that R^(1a), R^(1b), R^(4a), and R^(4b) cannot all be        hydrogen; and    -   further provided that when R^(1a), R^(1b), R^(4a), or R^(4b) is        C₁₋₆alkyl, the other substituent on the same carbon ring atom is        not hydrogen.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(I) or subformulae thereof, or a pharmaceutically acceptable salt orstereoisomer thereof; and one or more pharmaceutically acceptablecarriers.

In yet another aspect, the invention provides a combination, inparticular a pharmaceutical combination, comprising a therapeuticallyeffective amount of a compound of Formula (I) or subformulae thereof, ora pharmaceutically acceptable salt or stereoisomer thereof; and one ormore therapeutically active agent(s).

The compounds of the invention, alone or in combination with one or moretherapeutically active agent(s), can be used for treating, amelioratingor preventing acute joint damage or injury, such as arthritis(osteoarthritis, traumatic arthritis, systemic rheumatoid arthritis) ordegenerative disc disease. Furthermore, the compounds of the invention,alone or in combination with one or more therapeutically activeagent(s), can be used for inducing hyaline cartilage production or forinducing differentiation of chondrogenic progenitor cells into maturechondrocytes mature chondrocytes producing hyaline cartilageextracellular matrix.

Unless specified otherwise, the term “compounds of the presentinvention” refers to compounds of Formula (I) and subformulae thereof(e.g., Formula (1A), (1B), (1C), (1D), (1E), (1F), (1G), (1H), (1I),(1J), (1K), (1L), (2A), (2B), (2C), (2D), (2E), (2F), (2G), (2H), (2I),(2J), (2K), (2L)), and salts thereof, as well as all stereoisomers(including diastereoisomers and enantiomers), rotamers, tautomers andisotopically labeled compounds (including deuterium substitutions), aswell as inherently formed moieties.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel compounds that stimulate hyalinecartilage production in injured joints.

In one aspect, the present invention provides novel compounds andcompositions for repairing cartilage. Also provided are compositions andmethods to treat, prevent or ameliorate arthritis or joint injury byadministering a compound or composition of the invention into a joint, acartilage tissue or a cartilage proximal tissue, or systemically.Further, the invention provides compositions and methods for inductionof chondrogenic progenitor differentiation into normal hyalinechondrocytes.

Definitions

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “C₁₋₆alkoxy” refers to a radical of the formula—OR_(a) where R_(a) is a C₁₋₆ alkyl radical as generally defined above.Examples of C₁₋₆alkoxy include, but are not limited to, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy. The alkylportion of the alkoxy may be optionally substituted, and thesubstituents include those described for the alkyl group below.

As used herein, the term “C₁₋₆ alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to six carbon atoms,and which is attached to the rest of the molecule by a single bond. Theterm “C₁₋₄alkyl” is to be construed accordingly. Examples of C₁₋₆alkylinclude, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl and 1,1-dimethylethyl (t-butyl). Typicalsubstituents include, but are not limited to halo, hydroxyl, alkoxy,cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl, or an heteroform ofone of these groups, and each of which can be substituted by thesubstituents that are appropriate for the particular group.

“Amino”, as used herein, refers to the radical —NH₂. When an amino isdescribed as “substituted” or “optionally substituted”, the termincludes NR′R″ wherein each R′ and R″ is independently H, or is analkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkylcycloalkylalkyl group or a heteroform of one of these groups, and eachof the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or groups orheteroforms of one of these groups, each of which is optionallysubstituted with the substituents described herein as suitable for thecorresponding group. Unless otherwise indicated, the compounds of theinvention containing amino moieties may include protected derivativesthereof. Suitable protecting groups for amino moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

As used herein, the term “aminoC₁₋₆alkyl” refers to a C₁₋₆alkyl radicalas defined above, wherein one of the hydrogen atoms of the C₁₋₆alkylgroup is replaced by a primary amino group.

Representative examples of aminoC₁₋₆alkyl include, but are not limitedto, amino-methyl, 2-amino-ethyl, 2-amino-propyl, 3-amino-propyl,3-amino-pentyl and 5-amino-pentyl.

As used herein, the term “C₁₋₄alkylamino” refers to a radical of theformula —NH—R_(a) where R_(a) is a C₁₋₄alkyl radical as defined above.

“Aromatic”, as used herein, refers to a moiety wherein the constituentatoms make up an unsaturated ring system, where all atoms in the ringsystem are sp² hybridized and the total number of pi electrons is equalto 4n+2. An aromatic ring may be such that the ring atoms are onlycarbon atoms or may include carbon and non-carbon atoms (seeHeteroaryl).

“Aryl”, as used herein, refers to a monocyclic or polycyclic aromaticring assembly containing 6-14 ring atoms where all the ring atoms arecarbon atoms. Typically, the aryl is a 6-membered (ring atoms)monocyclic, a 10- to 12-membered bicyclic or a 14-membered fusedtricyclic aromatic ring system. Six to fourteen membered aryls include,but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, andanthracenyl. An aryl may be unsubstituted or substituted by 1-5 (such asone, or two, or three) substituents independently selected from thegroup consisting of hydroxy, thiol, cyano, nitro, C₁₋₄alkyl,C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, thioC₁₋₄alkyl, C₁₋₄alkenyloxy,C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl,di-C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl,C₁₋₄alkylaminosulfonyl, aryl, heteroaryl, cycloalkyl and heterocyclyl,wherein each of the afore-mentioned substitutents may be furthersubstituted by one or more substituents independently selected fromhalogen, alkyl, hydroxyl or C₁₋₄alkoxy groups. When an “aryl” isrepresented along with another radical like “arylalkyl”, “aryloxyalkyl”,“aryloxycarbonyl”, “aryloxy-carbonylalkyl”, the aryl portion shall havethe same meaning as described in the above-mentioned definition of“aryl”. “Bicyclic” or “bicyclyl”, as used here, in refers to a ringassembly of two rings where the two rings are fused together, linked bya single bond or linked by two bridging atoms. The rings may be acarbocyclyl, a heterocyclyl, or a mixture thereof.

“Bridging ring”, as used herein, refers to a polycyclic ring systemwhere two ring atoms that are common to two rings are not directly boundto each other. One or more rings of the ring system may also compriseheteroatoms as ring atoms. Non-exclusive examples of bridging ringsinclude norbornanyl, oxabicyclo[2.2.1]heptanyl,azabicyclo[2.2.1]heptanyl, adamantanyl, and the like.

“Cycloalkyl”, as used herein, means a radical comprising a non-aromatic,saturated monocyclic, bicyclic, tricyclic, fused, bridged or spiropolycyclic hydrocarbon ring system of 3- to 14-ring members where allthe ring members are carbon atoms. Exemplary monocyclic cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, and the like. Exemplarybicyclic cycloalkyls include bicyclo[2.2.1]heptane,bicyclo[3.2.1]octanyl, bornyl, norbornanyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl. Exemplary tricyclic cycloalkyl groups include, forexample, adamantanyl. A cycloalkyl may be unsubstituted or substitutedby one, or two, or three, or more substituents independently selectedfrom the group consisting of hydroxyl, thiol, cyano, nitro, oxo,alkylimino, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄thioalkyl, C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen,C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl where each of theafore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,alkoxy residues) may be further substituted by one or more residuesindependently selected at each occurrence from halogen, hydroxyl orC₁₋₄alkoxy groups.

“Cyano”, as used herein, refers to the radical —CN.

“EC₅₀”, as used herein, refers to the molar concentration of a modulatorthat produces 50% efficacy.

“IC₅₀”, as used herein, refers to the molar concentration of aninhibitor or modulator that produces 50% inhibition.

“Fused ring”, as used herein, refers to a multi-ring assembly whereinthe rings comprising the ring assembly are so linked that the ring atomsthat are common to two rings are directly bound to each other. The fusedring assemblies may be saturated, partially saturated, aromatics,carbocyclics, heterocyclics, and the like. Non-exclusive examples ofcommon fused rings include decalin, naphthalene, anthracene,phenanthrene, indole, benzofuran, purine, quinoline, and the like.

“Halo” or “halogen”, as used herein, refers to fluoro, chloro, bromo,and iodo.

“Halo-substituted C₁₋₆alkyl”, as used herein, refers to a C₁₋₆alkylradical as defined above, substituted by one or more halo radicals asdefined above. Examples of halo-substituted C₁₋₆alkyl include, but arenot limited to, trifluoromethyl, difluoromethyl, fluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl,3-bromo-2-fluoropropyl and 1,4,4-trifluorobutan-2-yl.

“Heteroaryl”, as used herein, refers to a 5- or 6-membered aromaticmonocyclic ring radical which comprises 1, 2, 3 or 4 heteroatomsindividually selected from nitrogen, oxygen and sulfur. The heteroarylradical may be bonded via a carbon atom or heteroatom. Examples ofheteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl. Aheteroaryl may be unsubstituted or substituted with one or moresubstituents independently selected from hydroxyl, thiol, cyano, nitro,C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, thioC₁₋₄alkyl,C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino,C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl where each of theafore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,alkoxy residues) may be further substituted by one or more residuesindependently selected at each occurrence from halogen, hydroxyl orC₁₋₄alkoxy groups. When a heteroaryl is represented along with anotherradical like “heteroaryloxy”, “heteroaryloxyalkyl”,“heteroaryloxycarbonyl”, the heteroaryl portion shall have the samemeaning as described in the above-mentioned definition of “heteroaryl”.

“Heteroatom”, as used herein, refers to an atom that is not a carbonatom. Particular examples of heteroatoms include, but are not limited tonitrogen, oxygen, and sulfur.

“Heterocyclyl” or “heterocyclic”, as used herein, refers to a stable 5-or 6-membered non-aromatic monocyclic ring radical which comprises 1, 2,or 3, heteroatoms individually selected from nitrogen, oxygen andsulfur. The heterocyclyl radical may be bonded via a carbon atom orheteroatom. Examples of heterocyclyl include, but are not limited to,azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl,tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl,morpholinyl or perhydroazepinyl.” A heterocyclyl may be unsubstituted orsubstituted with 1-5 substituents (such as one, or two, or three) eachindependently selected from hydroxyl, thiol, cyano, nitro, oxo,alkylimino, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy,C₁-4thioalkyl, C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen,C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl where each of theafore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,alkoxy residues) may be further substituted by one or more residuesindependently selected at each occurrence from halogen, hydroxyl orC₁₋₄alkoxy groups.

Hydroxy, as used herein, refers to the radical —OH.

“Protected derivatives”, as used herein, refers to derivatives ofinhibitors in which a reactive site or sites are blocked with protectinggroups. Protected derivatives are useful in the preparation ofinhibitors or in themselves may be active as inhibitors. Examples ofprotected group includes, but are not limited to, acetyl,tetrahydropyran, methoxymethyl ether, β-methoxyethoxymethyl ether,ρ-methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether,carbobenzyloxy, benzyl, tert-butoxycarbonyl, ρ-methoxyphenyl,9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals, dithianes,methylesters, benzyl esters, tert-butyl esters, and silyl esters. Acomprehensive list of suitable protecting groups can be found in T. W.Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley& Sons, Inc. 1999.

“Unsubstituted or substituted” or “optionally substituted”, as usedherein, indicate the substituent bound on the available valance of anamed group or radical. “Unsubstituted” as used herein indicates thatthe named group or radical will have no further non-hydrogensubstituents. “Substituted” or “optionally substituted” as used hereinindicates that at least one of the available hydrogen atoms of namedgroup or radical has been (or may be) replaced by a non-hydrogensubstituent. Unless otherwise specified, examples of substituents mayinclude, but are not limited to, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, C₁₋₆alkoxy, 6- to 10-membered aryloxy, 5- to 10-memberedheteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,C₁₋₆alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, C₁₋₆alkyl,C₁₋₆haloalkyl, hydroxyC₁₋₆alkyl, carbonylC₁₋₆alkyl,thiocarbonylC₁₋₁₀alkyl, sulfonylC₁₋₆alkyl, sulfinylC₁₋₆alkyl,C₁₋₁₀azaalkyl, iminoC₁₋₆alkyl, 3- to 12-membered cycloalkylC₁₋₆alkyl, 4-to 15-membered heterocycloalkylC₁₋₆alkyl, 6- to 10-memberedarylC₁₋₆alkyl, 5- to 10-membered heteroarylC₁₋₆alkyl, 10- to 12-memberedbicycloarylC₁₋₆alkyl, 9- to 12-membered heterobicycloarylC₁₋₆alkyl, 3-to 12-membered cycloalkyl, 4- to 12-membered heterocyclyl, 9- to12-membered bicycloalkyl, 3- to 12-membered heterobicycloalkyl, 6- to12-membered aryl, and 5- to 12-membered heteroaryl,

“Sulfonyl”, as used herein, means the radical —S(O)₂—. It is noted thatthe term “sulfonyl” when referring to a monovalent substituent canalternatively refer to a substituted sulfonyl group, —S(═O)₂R, where Ris hydrogen or a non-hydrogen substituent on the sulfur atom formingdifferent sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkoxyalkyl wouldrepresent an alkoxy group attached to the parent molecule through analkyl group.

As used herein, the term “chondrocytes” refers to differentiatedcartilage cells. Chondrocytes produce and maintain the cartilaginousmatrix which is composed of collagen and proteoglycans. Chondrocytes arederived from the differentiation of chondrogenic progenitor cells(CPCs). Differentiation is the process a specialized cell type is formedfrom a less specialized cell type, for example, a chondrocyte from achondrogenic progenitor cell (CPC).

As used herein, the term “chondrocyte differentiation agent” refers toan agent that induces chondrogenic cells to differentiate into maturechondrocyte, which then synthesize the cartilage extra-cellular matrix(ECM).

As used herein, the term “subject” refers to primates (e.g., humans,male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. Incertain embodiments, the subject is a primate. In yet other embodiments,the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers to alleviating or ameliorating the disease ordisorder (i.e., slowing or arresting the development of the disease orat least one of the clinical symptoms thereof); or alleviating orameliorating at least one physical parameter or biomarker associatedwith the disease or disorder, including those which may not bediscernible to the patient.

As used herein, the term “prevent”, “preventing” or “prevention” of anydisease or disorder refers to the prophylactic treatment of the diseaseor disorder; or delaying the onset or progression of the disease ordisorder As used herein, a subject is “in need of” a treatment if suchsubject would benefit biologically, medically or in quality of life fromsuch treatment.

As used herein, the term “a therapeutically effective amount” of acompound of the present invention refers to an amount of the compound ofthe present invention that will elicit the biological or medicalresponse of a subject, for example, reduction or inhibition of an enzymeor a protein activity, or ameliorate symptoms, alleviate conditions,slow or delay disease progression, or prevent a disease, etc. In onenon-limiting embodiment, the term “a therapeutically effective amount”refers to the amount of the compound of the present invention that, whenadministered to a subject, is effective to (1) at least partiallyalleviate, inhibit, prevent and/or ameliorate joint damage resultingfrom joint injury and arthritis. In another non-limiting embodiment, theterm “a therapeutically effective amount” refers to the amount of thecompound of the present invention that, when administered to a cell, ora tissue, or a non-cellular biological material, or a medium, iseffective to promote chondrogenesis.

As used herein, the terms “treat”, “treating”, “treatment” plus“ameliorate” and “ameliorating” refer to any indicia of success in thetreatment or amelioration of an injury, pathology, condition, or symptom(e.g., pain), including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the symptom,injury, pathology or condition more tolerable to the patient; decreasingthe frequency or duration of the symptom or condition; or, in somesituations, preventing the onset of the symptom or condition. Thetreatment or amelioration of symptoms can be based on any objective orsubjective parameter; including, e.g., the result of a physicalexamination.

As used herein, “administering” refers to administration to a specificjoint.

As used herein, the term “pharmaceutical composition” refers to acompound of the invention, or a pharmaceutically acceptable saltthereof, together with at least one pharmaceutically acceptable carrier,in a form suitable for oral or parenteral administration.

As used herein, the term “pharmaceutically acceptable carrier” refers toa substance useful in the preparation or use of a pharmaceuticalcomposition and includes, for example, suitable diluents, solvents,dispersion media, surfactants, antioxidants, preservatives, isotonicagents, buffering agents, emulsifiers, absorption delaying agents,salts, drug stabilizers, binders, excipients, disintegration agents,lubricants, wetting agents, sweetening agents, flavoring agents, dyes,and combinations thereof, as would be known to those skilled in the art(see, for example, Remington The Science and Practice of Pharmacy,22^(nd) Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

Description of Preferred Embodiments

The present invention relates to compositions and methods for treatingor preventing joint damage resulting from joint injury and arthritis.

Various enumerated embodiments of the invention are described herein.Features specified in each embodiment may be combined with otherspecified features to provide further embodiments of the presentinvention.

In one aspect, the present invention provides a compound of Formula (I),or a pharmaceutically acceptable salt or stereoisomer thereof, asdescribed above.

Embodiment 1. A compound of Formula (I), or a pharmaceuticallyacceptable salt or stereoisomer thereof;

-   -   wherein R⁰ is hydrogen or C₁₋₆alkyl;    -   R² is phenyl; a 5- or 6-membered heteroaryl or a 5- or        6-membered heterocyclyl, each having 1 to 3 heteroatoms selected        from N, O and S; wherein R² is unsubstituted or substituted by 1        to 3 substituents independently selected from halo, C₁₋₆alkyl,        halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted        C₁₋₆alkoxy, cyano, C₁₋₆alkylsulfonyl, phenyl unsubstituted or        substituted by halo;    -   R³ is a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms        selected from N, O and S; wherein R³ is unsubstituted or        substituted by 1 to 3 substituents independently selected from        halo, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy or        —NR⁵R⁶;    -   R^(1a), R^(1b), R^(4a), and R^(4b) are each independently        hydrogen, halo, hydroxyl, C₁₋₆alkoxy, C₁₋₆alkyl, —NR⁷R⁸ or        —NR⁷—(CR⁹R¹⁰)₂₋₄—OR¹¹; or wherein one of R^(1a) and R^(1b)        together with one of R^(4a) and R^(4b) form a cyclopropyl with        the two carbon atoms to which said R^(1a), R^(1b), R^(4a) and        R^(4b) are respectively attached;    -   R⁵, R⁶, R⁷, R⁹, R¹⁰ and R¹¹ are each independently hydrogen or        C₁₋₆alkyl;    -   R⁸ is hydrogen, C₃₋₇ cycloalkyl or a 5- or 6-membered        heterocyclyl having 1-3 heteroatoms selected from N, O and S;        wherein said C₃₋₇ cycloalkyl or 5- or 6-membered heterocyclyl of        R⁸ is unsubstituted or substituted by hydroxy or C₁₋₆ alkyl;    -   alternatively, R⁵ and R⁶ or R⁷ and R⁸ together with the nitrogen        atom to which they are attached in —NR⁵R⁶ or —NR⁷R⁸ respectively        form a 5- or 6-membered heterocyclyl having 1-3 heteroatoms        selected from N, O and S;    -   provided that R^(1a), R^(1b), R^(4a), and R^(4b) cannot all be        hydrogen; and    -   further provided that when R^(1a), R^(1b), R^(4a), or R^(4b) is        C₁₋₆alkyl, the other substituent on the same carbon ring atom is        not hydrogen.

Embodiment 2. A compound according to Embodiment 1, selected fromFormula (1A), (1B), (1C), (1D), (1E), (1F), (1G), (1H), (1I), (1J),(1K), (1L), (2A), (2B), (2C), (2D), (2E), (2F), (2G), (2H), (2I), (2J),(2K) and (2L), or a pharmaceutically acceptable salt, or stereoisomerthereof;

Embodiment 3. A compound according to Embodiment 2, selected from:

-   -   (a) Formula (1A) or (2A);    -   (b) Formula (1B) or (2B);    -   (c) Formula (1C) or (2C);    -   (d) Formula (1D) or (2D);    -   (e) Formula (1E) or (2E);    -   (f) Formula (1F) or (2F);    -   (g) Formula (1G) or (2G)    -   (h) Formula (1H) or (2H);    -   (i) Formula (1I) or (2I);    -   (j) Formula (1J) or (2J);    -   (k) Formula (1K) or (2K); and    -   (I) Formula (1L) or (2L);    -   or a pharmaceutically salt, or stereoisomer thereof; wherein        various substituents are as defined in any of the above        embodiments.

Embodiment 3A. A compound according to Embodiment 3, of Formula (1A) orFormula (2A).

Embodiment 3B. A compound according to Embodiment 3, of Formula (1 B) orFormula (2B).

Embodiment 3C. A compound according to Embodiment 3, of Formula (1C) orFormula (2C).

Embodiment 3D. A compound according to Embodiment 3, of Formula (1D) orFormula (2D).

Embodiment 3E. A compound according to Embodiment 3, of Formula (1E) orFormula (2E).

Embodiment 3F. A compound according to Embodiment 3, of Formula (1F) orFormula (2F).

Embodiment 3G. A compound according to Embodiment 3, of Formula (1G) orFormula (2G).

Embodiment 3H. A compound according to Embodiment 3, of Formula (1H) orFormula (2H).

Embodiment 3I. A compound according to Embodiment 3, of Formula (1I) orFormula (2I).

Embodiment 3J. A compound according to Embodiment 3, of Formula (1J) orFormula (2J).

Embodiment 3K. A compound according to Embodiment 3, of Formula (1K) orFormula (2K).

Embodiment 3L. A compound according to Embodiment 3, of Formula (1 L) orFormula (2L).

Embodiment 4. A compound according to Embodiment 2, selected fromFormula (1A), (1C), (1E), (1F), (1G), (1I), (1L), (1K), (2A), (2C),(2E), (2F), (2G), (2I), (2K) and (2L), or a pharmaceutically acceptablesalt, or stereoisomer thereof.

Embodiment 5. A compound according to Embodiment 2, selected fromFormula (1A), (1C), (1G), (1L), (2A), (2C), (2G) and (2L), or apharmaceutically acceptable salt, or stereoisomer thereof; whereinvarious substituents are as defined in any of the above embodiments. Insome embodiments, R^(1a) and R^(4a) are hydroxyl.

Embodiment 5A. A compound according to Embodiment 5, selected fromFormula (1A), (1G), (2A) and (2G), or a pharmaceutically acceptable saltor stereoisomer thereof; wherein various substituents are as defined inany of the above embodiments. In some embodiments, R^(1a) and R^(4a) arehydroxyl.

Embodiment 5B. A compound according to Embodiment 5, of Formula (2A) or(2G), or a pharmaceutically acceptable salt or stereoisomer thereof;wherein various substituents are as defined in any of the aboveembodiments. In some embodiments, R^(1a) and R^(4a) are hydroxyl.

Embodiment 6. A compound according to any of the above Embodiments, or apharmaceutically acceptable salt or stereoisomer thereof; wherein R¹,R^(1b), R^(4a), and R^(4b) are each independently hydrogen, halo,hydroxyl, C₁₋₆alkoxy, —NR⁷R⁸ or —NR⁷—(CR⁹R¹⁰)₂₋₄—OR¹¹; or wherein one ofR^(1a) and R^(1b) together with one of R^(4a) and R^(4b) form acyclopropyl with the two carbon atoms to which said R¹, R^(1b), R^(4a)and R^(4b) are respectively attached.

Embodiment 7. compound according to Embodiment ^(a)6, or apharmaceutically acceptable salt or stereoisomer thereof; wherein one ofR^(1a) and R^(1b) is hydrogen and the other is hydroxyl, fluoro,methoxy, methylamino, (2-hydroxyethyl)amino, di-methylamino,morpholin-4-yl, methyl, ((tetrahydro-2H-pyran-4-yl)amino) or(3-hydroxycyclobutyl)amino.

Embodiment 8. compound according to Embodiment 7, or a pharmaceuticallyacceptable salt or stereoisomer thereof; wherein one of R^(1a) andR^(1b) is hydrogen and the other hydroxyl; and R^(4a) and R^(4b) arehydrogen.

Embodiment 9. A compound according to Embodiment 64 or 5, or apharmaceutically acceptable salt or stereoisomer thereof; wherein R^(1a)and R^(1b) are hydrogen, and one of R^(4a) and R^(4b) is hydrogen andthe other is hydroxyl or fluoro.

Embodiment 10. A compound according to Embodiment 6, or apharmaceutically acceptable salt or stereoisomer thereof; wherein one ofR^(1a) and R^(1b) and one of R^(4a) and R^(4b) together with the carbonring atoms form a cyclopropyl fused to the bicyclic ring.

Embodiment 11. A compound according to any one of the above Embodiments,or a pharmaceutically acceptable salt or stereoisomer thereof; whereinR² is phenyl, pyridyl, pyrazolyl, thiazolyl or piperidinyl, each ofwhich is unsubstituted or substituted by 1 to 2 substituentsindependently selected from halo, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy, cyano, C₁₋₆alkylsulfonyl,phenyl unsubstituted or substituted by halo.

Embodiment 11A. A compound according to Embodiment 11, wherein R² isphenyl substituted by 1-2 substituents independently selected fromchloro, fluoro, trifluoromethyl, trifluoromethoxy, cyano andhalo-substituted phenyl.

Embodiment 11B. A compound according to Embodiment 11, wherein R² ispyridyl substituted by 1-2 substituents independently selected fromchloro, methyl, methoxy and trifluoromethyl, Embodiment 11C. A compoundaccording to Embodiment 11, wherein R² is pyrazolyl or thiazolyl, eachsubstituted by methyl.

Embodiment 11D. A compound according to Embodiment 11, wherein R² ispyridinyl substituted by methylsulfonyl.

Embodiment 12. A compound according to Embodiment 11, or apharmaceutically acceptable salt or stereoisomer thereof; wherein R² isselected from:

-   phenyl substituted by 3,4-dichloro; 2-trifluoromethyl;    3-trifluoromethyl; 3-cyano-4-chloro;-   2-cyano-4-chloro; 3-fluoro-4-chloro; 3-trifluoromethoxy;    3-fluoro-4-trifluoromethoxy; or 3-chloro-4-(2-fluorophenyl);-   pyridin-4-yl substituted by 6-methoxy or 2-trifluoromethyl;-   pyridin-3-yl substituted by 5,6-dichloro; 6-methoxy;    5-chloro-6-methyl or 5-trifluoromethyl-6-methyl;-   pyridin-2-yl substituted by 4,5-dichloro;-   1H-pyrazol-3-yl substituted 1-methyl;-   thiazol-2-yl substituted by 5-methyl; and-   piperidin-4-yl substituted by 1-methylsulfonyl.

Embodiment 13. A compound according to any one of the above Embodiments,or a pharmaceutically acceptable salt or stereoisomer thereof; whereinR³ is pyridyl, pyrimidinyl or pyrazolyl, each of which is unsubstitutedor substituted by 1 to 2 substituents independently selected from halo,C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy or —NR⁵R⁶.

Embodiment 13A. A compound according to Embodiment 13, wherein R³ ispyridyl unsubstituted or substituted by 1 to 2 substituentsindependently selected from fluoro, trifluoromethyl, methyl and methoxy.

Embodiment 13B. A compound according to Embodiment 13, wherein R³ ispyrimidyl unsubstituted or substituted by 1 to 2 substituentsindependently selected from fluoro, trifluoromethyl, methyl, amino,di-methylamino and morpholinyl. Embodiment 13C. A compound according toEmbodiment 13, wherein R³ is 1-methyl-1H-pyrazo-4-lyl or1-methyl-1H-pyrazol-3-yl.

Embodiment 14. A compound according to Embodiment 13, or apharmaceutically acceptable salt or stereoisomer thereof; wherein R³ isselected from:

-   4-pyridyl unsubstituted or substituted by 2-methyl;    2-trifluoromethyl; 2-methoxy; 2-amino;-   2-fluoro; 2,3-difluoro; or 2,5-difluoro;-   3-pyridyl unsubstituted or substituted by 6-methyl; 6-methoxy; or    5,6-dichloro;-   2-pyridyl substituted by 6-trifluoromethyl;-   pyrimidin-5-yl unsubstituted or substituted by 2-fluoro, 2-methyl,    2-amino, 2-trifluoromethyl, 2-morpholinyl or 2-di-methylamino;-   pyrimidin-4-yl substituted by 2-methyl; and-   1H-pyrazol-4-yl or 1H-pyrazolyl-3-yl substituted by 1-methyl.

Embodiment 15. A compound according to Embodiment 1, or apharmaceutically acceptable salt or stereoisomer thereof; wherein thecompound is selected from compounds 1-181 in Table 3.

Embodiment 15A. A compound according to Embodiment 1, or apharmaceutically acceptable salt or stereoisomer thereof; wherein thecompound is selected from:

-   (1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide;-   (1R,2R,4S,5S,6R,7R)—N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide;-   (1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide;    and-   (1S,2R,3S,4R,5S,6R)—N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide.

Embodiment 16. A compound of Formula (I) according to Embodiment 15 or15A, wherein said compound is a monohydrate.

Embodiment 17. A pharmaceutical composition comprising a compoundaccording to any one of the above Embodiments 1-16 and sub-embodiments,or a pharmaceutically acceptable salt or stereoisomer thereof, and oneor more pharmaceutically acceptable carriers.

Embodiment 18. A combination comprising a compound according to any oneof the above Embodiments 1-16 and sub-embodiments, or a pharmaceuticallyacceptable salt or stereoisomer thereof, and one or more therapeuticallyactive agents.

Embodiment 19. A compound according to any one of Embodiments 1-16 andsub-embodiments, or a pharmaceutically acceptable salt or enantiomerthereof, and optionally in combination with a second therapeutic agent;for use in treating, ameliorating or preventing arthritis or jointinjury in a mammal; or for cartilage repair.

Embodiment 20. Use of a compound according to any one of Embodiments1-16 and sub-embodiments, or a pharmaceutically acceptable salt orenantiomer thereof, and optionally in combination with a secondtherapeutic agent; in the manufacture of a medicament for arthritis orjoint injury, or for cartilage repair.

Embodiment 21. A method for treating, ameliorating or preventingarthritis or joint injury, or for cartilage repair in a mammal in needthereof, comprising administering a therapeutically effective amount ofa compound according to any one of Embodiments 1-16 and sub-embodiments,and optionally in combination with a second therapeutic agent; therebytreating, ameliorating or preventing arthritis or joint damage, orrepairing cartilage in said mammal.

Embodiment 22. The compound according to Embodiment 19, the useaccording to Embodiment 20, or the method according to Embodiment 21,wherein the arthritis is osteoarthritis, trauma arthritis, or autoimmunearthritis.

Embodiment 23. The method according to Embodiment 21, wherein saidcompound is administered orally.

Embodiment 24. A method of inducing hyaline cartilage production or amethod of inducing differentiation of chondrogenic progenitor cells intomature chondrocytes, comprising contacting chondrogenic progenitor cellswith a therapeutically effective amount of a compound according to anyone of Embodiments 1-16 and sub-embodiments, and optionally incombination with a second therapeutic agent; thereby inducingdifferentiation of chondrocyte progenitor cells into mature chondrocytesproducing hyaline cartilage extracellular matrix.

Embodiment 25. The method according to Embodiment 24, wherein saidcontacting step is performed in vitro or in vivo in a mammal; and whenin vivo, stem cells are present in the mammal.

Embodiment 26. The method according to Embodiment 24 or 25, wherein saidcontacting step occurs in a matrix or biocompatible scaffold.

Embodiment 27. The compound according to Embodiment 19, the useaccording to Embodiment 20, or the method according to any one ofEmbodiments 21-26, wherein said second therapeutic agent is achondrocyte differentiation agent.

Embodiment 28. The compound according to Embodiment 19, the useaccording to Embodiment 20, or the method according to any one ofEmbodiments 21-26, wherein said second therapeutic agent is selectedfrom angiopoietin-like 3 protein (ANGPTL3), insulin growth factor(IGF1), SM04690, Janus kinase inhibitor, oral salmon calcitonin,SD-6010, vitamin D3, collagen hydrolyzate, bone morphogenetic protein 7(BMP7), rusalatide acetate, avocado soy unsaponifiables (ASU), asteroid, a non-steroidal anti-inflammatory agent (NSAID), hyaluronicacid, kartogenin, TPX-100, and a compound having Formula (II);

-   -   or a pharmaceutically acceptable salt, or a stereoisomer        thereof, wherein    -   R¹ is phenyl or 5- or 6-membered heteroaryl; and R¹ is        unsubstituted or substituted by 1 to 2 substituents        independently selected from halo, cyano, C₁₋₆alkyl,        C₁₋₄haloalkyl, —C(O)R¹³, —C(O)OR¹³, —NR^(14a)R^(14b), 5- and        6-membered heterocyclyl, phenyl, and 5- and 6-membered        heteroaryl;    -   wherein R¹³ is C₁₋₆alkyl or amino; R^(14a) and R^(14b) are        independently is selected from hydrogen, C₁₋₆alkyl, —C(O)R¹⁵,        and —C(O)OR¹⁵; and R¹⁵ is C₁₋₄alkyl; and    -   wherein said heterocyclyl, phenyl, or heteroaryl substituent of        R¹ is unsubstituted or substituted by 1 to 2 substituents        independently selected from halo, hydroxy, and C₁₋₆alkyl;    -   R³ is phenyl or 5- or 6-membered heteroaryl; and R³ is        unsubstituted or substituted by 1 to 2 substituents        independently selected from halo, cyano, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —C(O)R¹⁶, —C(O)OR¹⁶,        5- and 6-membered heterocyclyl, and phenyl; wherein R¹⁶ is        C₁₋₆alkyl; and said heterocyclyl or phenyl of R³ is        unsubstituted or substituted by 1 to 2 substituents selected        from halo and cyano;    -   R² and R⁴ are independently hydrogen or C₁₋₆alkyl; or R² and R⁴        taken together form a cyclopropyl fused to the bicyclic ring, or        R² and R⁴ taken together form a bond, producing a double bond        between the two carbons to which R² and R⁴ are attached.

Embodiment 29. The compound according to Embodiment 19, the useaccording to Embodiment 20, or the method according to any one ofEmbodiments 21-26, wherein said compound having Formula (II) is selectedfrom:

-   (1R,2S,3R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1S,2R,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;-   (1S,2S,3R,4R)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide-   (1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide-   N-(2-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-3-(1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide-   (1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide-   (1S,2S,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide-   (1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide-   (1R,2R,4S,5S)—N-(3,4-dichlorophenyl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide-   (1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;    and-   N-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide.

Embodiment 30. A compound having Formula (III):

-   -   wherein Ak is C₁₋₆ alkyl;    -   R³ is a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms        selected from N, O and S; wherein R³ is unsubstituted or        substituted by 1 to 3 substituents independently selected from        halo, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy or        —NR⁵R⁶;    -   R^(1a), R^(1b), R^(4a), and R^(4b) are each independently        hydrogen, halo, hydroxyl, C₁₋₆alkoxy, C₁₋₆alkyl, —NR⁷R⁸ or        —NR⁷—(CR⁹R¹⁰)₂₋₄—OR¹¹; or wherein one of R^(1a) and R^(1b)        together with one of R^(4a) and R^(4b) form a cyclopropyl with        the two carbon atoms to which said R^(1a), R^(1b), R^(4a) and        R^(4b) are respectively attached;    -   R⁵, R⁶, R⁷, R⁹, R¹⁰ and R¹¹ are each independently hydrogen or        C₁₋₆alkyl;    -   R⁸ is hydrogen, C₃₋₇ cycloalkyl or a 5- or 6-membered        heterocyclyl having 1-3 heteroatoms selected from N, O and S;        wherein said C₃₋₇ cycloalkyl or 5- or 6-membered heterocyclyl of        R⁸ is unsubstituted or substituted by hydroxy or C₁₋₆ alkyl;    -   alternatively, R⁵ and R⁶ or R⁷ and R⁸ together with the nitrogen        atom to which they are attached in —NR⁵R⁶ or —NR⁷R⁸ respectively        form a 5- or 6-membered heterocyclyl having 1-3 heteroatoms        selected from N, O and S;    -   provided that R^(1a), R^(1b), R^(4a), and R^(4b) cannot all be        hydrogen; and    -   further provided that when R^(1a), R^(1b), R^(4a), or R^(4b) is        C₁₋₆alkyl, the other substituent on the same carbon ring atom is        not hydrogen.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possiblestereoisomers or as mixtures thereof, for example as pure opticalisomers, or as stereoisomer mixtures, such as racemates anddiastereoisomer mixtures, depending on the number of asymmetric carbonatoms. The present invention is intended to encompass all such possiblestereoisomers, including racemic mixtures, diasteriomeric mixtures andoptically pure forms. Optically active (R)- and (S)-stereoisomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturateddouble bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible stereoisomers, rotamers,atropisomers, tautomers or mixtures thereof, for example, assubstantially pure geometric (cis or trans) stereoisomers,diastereomers, optical isomers (antipodes), racemates or mixturesthereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Unless otherwise indicated, a compound represented herein as a singlestereoisomer includes an enantiomeric mixture (e.g., the enantiomer ofthe depicted compound and mixtures of the enantiomers). Furthermore,where a compound is described as a single regioisomer, it is understoodthat a sample of the compound may still contain small amounts of theother regioisomer and may also exist as an enantiomeric mixture.Typically, where a compound is described as a single regioisomer orenantiomer, the specified structure accounts for at least 90% by weightof total weight of depicted compound plus its isomers; preferably, thespecified isomer, diastereomer or enantiomer accounts for at least 95%by weight of the total weight including other isomers.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Isotopes that can be incorporated intocompounds of the invention include, for example, isotopes of hydrogen.

Further, incorporation of certain isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index ortolerability. It is understood that deuterium in this context isregarded as a substituent of a compound of the formula (I). Theconcentration of deuterium, may be defined by the isotopic enrichmentfactor. The term “isotopic enrichment factor” as used herein means theratio between the isotopic abundance and the natural abundance of aspecified isotope. If a substituent in a compound of this invention isdenoted as being deuterium, such compound has an isotopic enrichmentfactor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom), at least4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation). Itshould be understood that the term “isotopic enrichment factor” can beapplied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as 3H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I respectively. Accordingly itshould be understood that the invention includes compounds thatincorporate one or more of any of the aforementioned isotopes, includingfor example, radioactive isotopes, such as ³H and ¹⁴C, or those intowhich non-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or labeled compound may be particularlydesirable for PET or SPECT studies. Isotopically-labeled compounds offormula (I) can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

The compounds of the present invention are either obtained in the freeform, as a salt thereof. As used herein, the terms “salt” or “salts”refers to an acid addition or base addition salt of a compound of theinvention. “Salts” include in particular “pharmaceutical acceptablesalts”. The term “pharmaceutically acceptable salts” refers to saltsthat retain the biological effectiveness and properties of the compoundsof this invention and, which typically are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, ammonium salts and metals from columns Ito XII of the periodic table. In certain embodiments, the salts arederived from sodium, potassium, ammonium, calcium, magnesium, iron,silver, zinc, and copper; particularly suitable salts include ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike. Certain organic amines include isopropylamine, benzathine,cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazineand tromethamine.

In another aspect, the present invention provides compounds of thepresent invention in acetate, ascorbate, adipate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate,hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate,malate, maleate, malonate, mandelate, mesylate, methylsulphate, mucate,naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate,oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate,sulfosalicylate, sulfate, tartrate, tosylate trifenatate,trifluoroacetate or xinafoate salt form.

Processes for Making Compounds of the Invention

All methods described herein can be performed in any suitable order,unless otherwise indicated or otherwise clearly contradicted by context.

Compounds of Formula (1A)-(1L) and Formula (2A)-(2L) can be prepared asgenerally illustrated in Schemes 1-7, wherein R¹ encompasses R^(1a),R^(1b), R^(4a) and R^(4b) groups that are attached to ring carbons 5 or6; Ar encompasses R³ aryl and heteroaryl groups; and R^(1a), R^(1b), R²,R³, R^(4a), R^(4b), R⁵ and R⁶ are defined as above. In the schemesbelow, the formula depicted as Formula (1A)-(1L)* and Formula (2A)-(2L)*includes a mixture of the formulae as shown and their correspondingenantiomers and regioisomers.

Intermediate GS1b can be prepared from commercially available methylpropiolate, GS1a, via bromination and Diels-Alder reaction with furan.Intermediate GS1c can be prepared via functionalization of GSb1utilizing reactions including but not limited to cyclopropanation andhydroboration/oxidation followed by further functionization includingmethylation, fluorination, oxidation and reduction. Intermediates GS1dand GS1e can be prepared from GS1c by debromination and conjugateaddition. Subsequent amide bond formation can afford compounds ofFormula (1A)-(1L)* and Formula (2A)-(2L)*. Alternatively, amide bondformation and debromination of GS1c can afford GS1f, which afterconjugate addition can provide compounds of Formula (1A)-(1L)* andFormula (2A)-(2L)*.

In Scheme 2, bromination of methyl propiolate, 1a, usingN-bromosuccinimide or a similar brominating reagent in the presence of asilver catalyst such as silver nitrate afforded intermediate 1b.Diels-Alder cycloaddition of 1b in excess furan with mild heating (ca.80° C.) provided intermediate 1c. Cyclopropanation of 1c usingdiethylzinc and diiodomethane afforded intermediate 1d. Hydroboration of1c using borane-tetrahydrofuran complex followed by oxidation withhydrogen peroxide afforded intermediate 1e as a mixture of alcoholregioisomers. Methylation of 1e using silver oxide and iodomethaneprovided If as a mixture of methoxy regioisomers. Fluorination of 1eusing DAST afforded 1g as a mixture of fluorine regioisomers. Oxidationof 1e using DMP afforded 1h as a mixture of ketone regioisomers.Reduction of 1h with sodium borohydride provided 1i as a mixture ofalcohol regioisomers. Fluorination of 1i using DAST afforded 1j as amixture of fluorine regioisomers.

In Scheme 3, debromination of intermediate 1d-j using zinc and aceticacid afforded 2a as a mixture of regioisomers. 1,4-conjugate additionreaction of 2a using an aryl boronic ester or acid with a rodiumcatalyst in the presence of a base such as potassium carbonate and aligand such as BINAP afforded 2b and 2c as mixtures of regioisomers.Amide bond formation using 2b, trimethylaluminum and an amine or anilineprovided compounds of Formula (1A)-(1L)* as a mixture of regioisomers.Amide bond formation using 2c, LiHMDS and an amine or aniline providedcompounds of Formula (2A)-(2L)* as a mixture of regioisomers.

In Scheme 4, amide bond formation using 1d-j, trimethylaluminum and ananiline provided 3a as a mixture of regioisomers. Debromination ofintermediate 3a using zinc and acetic acid afforded 3b as a mixture ofregioisomers. 1,4-conjugate addition reaction of 3b using an arylboronic ester or acid with a rodium catalyst in the presence of a basesuch as potassium carbonate and a ligand such as BINAP affordedcompounds of Formula (1A)-(1L)* and Formula (2A)-(2L)* as mixtures ofregioisomers.

In Scheme 5, compounds 4b of Formula I can be prepared from 4a viafluorination using XtalFluor-E and triethylamine trihydrofluoride.

In Scheme 6, dihydroxylation of 1c using osmium tetroxide andN-methylmorpholine N-oxide afforded 5a. Protection of the diol in 5ausing (dimethoxymethyl)benzene afforded 5b. Amide bond formation using5b, trimethylaluminum and an aniline provided 5c. Debromination ofintermediate 5c using zinc and acetic acid afforded 5d. 1,4-conjugateaddition reaction of 5d using an aryl boronic ester or acid with arodium catalyst in the presence of a base such as potassium carbonateand a ligand such as BINAP afforded intermediates 5e and 5f.Intermediates 5e and 5f were deprotected using boron trichloride toafford 5g and 5h respectively.

In Scheme 7, fluorination of 6a using XtalFluor-E and triethylaminetrihydrofluoride afforded 6b. Oxidation of 6a using DMP afforded 6c.Reductive amination on 6c using an amine and sodium borohydride afforded6d. Treatment of 6c with methylmagnesium bromide provided 6e. Reductionof 6c using sodium borohydride afforded 6f.

The invention further includes any variant of the present processes; forexample, wherein an intermediate product obtainable at any stage thereofis used as starting material and the remaining steps are carried out;wherein starting materials are formed in situ under the reactionconditions; or wherein the reaction components are used in the form oftheir salts or optically pure material. Compounds of the invention andintermediates can also be converted into each other according to methodsgenerally known to those skilled in the art.

Pharmacology and Utility

The present invention provides a method of treating, ameliorating orpreventing arthritis of joint injury in a mammal in need thereof, themethod including administering to the mammal a therapeutically effectiveamount of a compound of the invention, wherein the subject has or is atrisk of joint damage or arthritis. The invention also provides a methodof treating, ameliorating or preventing arthritis or joint injury in ahuman patient, the method comprising: administering orally the patient acomposition comprising an effective amount of a compound of theinvention, thereby treating, ameliorating or preventing arthritis orjoint injury in the patient. In some embodiments, the patient hasarthritis or joint injury. In some embodiments, the individual does nothave, but is at risk for, arthritis or joint injury. In someembodiments, the arthritis is osteoarthritis, trauma arthritis, orautoimmune arthritis.

The compounds of the present invention are also useful for inducinghyaline cartilage production of chondrogenic progenitor cells. In someembodiment, the present invention provides a method for preventingchondrocyte hypertrophy of chondrocytic progenitor cells. In someembodiment, the present invention provides a method of inducingdifferentiation of chondrogenic progenitor cells into maturechondrocytes, the method including contacting chondrogenic progenitorcells with a sufficient amount of a compound of the invention, therebyinducing differentiation into mature chondrocytes producing hyalinecartilage extracellular matrix.

CPCs can differentiate into different types of cells including, but notlimited to, osteoblasts, hyaline chondrocytes and hypertrophicchondrocytes. Differentiation is the process by which a specialized celltype is formed from a less specialized cell type, for example, achondrocyte from a chondrogenic progenitor. In some embodiments, themethod is performed in vitro. In some embodiments, the method isperformed in vivo in a mammal and the progenitor cells are present inthe mammal.

Inducing chondrocyte differentiation of chondrogenic progenitor can beaccomplished using any suitable amount of a compound of the presentinvention. In some embodiment, the compound of the present invention canbe present in an amount form about 0.1 mg to about 10000 mg, e.g., 1.0mg to 1000 mg, e.g., 10 mg to 500 mg, according to the particularapplication and potency of the active component. In some embodiments,the compounds of the present invention can be administered orally oncedaily at a dose of 1 mg/kg to about 300 mg/kg. Treatment duration canvary from a week or less to chronic treatment in severe osteoarthritis.

It is contemplated that compounds, compositions, and methods of thepresent invention may be used to treat, ameliorate or prevent any typeof articular cartilage damage (e.g., joint damage or injury) including,for example, damage arising from a traumatic event or tendon or ligamenttear. In some embodiments, the compounds or compositions of theinvention are administered to prevent or ameliorate arthritis or jointdamage, for example where there is a genetic or family history ofarthritis or joint damage or joint injury or prior or during jointsurgery. In some embodiments, compounds, compositions and methods areused to treat joint damage. In particular embodiments, the joint damageis traumatic joint injury. In other embodiments, the joint damage isdamage arising from age or inactivity. In yet other embodiments, thejoint damage is damage arising from an autoimmune disorder. In otherembodiments, the joint damage is damage arising from a metabolicdisorder (e.g. diabetes). In some embodiments of the invention,compounds, compositions, and methods of the present invention may beused to treat, ameliorate or prevent osteoarthritis. In someembodiments, the compounds, compositions and methods are used toameliorate or prevent arthritis in a subject at risk of having oracquiring arthritis. In some embodiments, the compounds, compositionsand methods are used to ameliorate or prevent joint damage in a subjectat risk of having or acquiring joint damage.

In some embodiments, compounds, compositions, and methods of the presentinvention provide a method for stimulating chondrocyte proliferation andhyaline cartilage production in cartilagenous tissues that have beendamaged, e.g., due to traumatic injury or chondropathy. In particularembodiments compounds, compositions, and methods of the presentinvention are useful for treatment of cartilage damage in joints, e.g.,at articulated surfaces, e.g., spine, shoulder, elbow, wrist, joints ofthe fingers, hip, knee, ankle, and joints of the feet. Examples ofdiseases or disorders that may benefit from treatment includeosteoarthritis, rheumatoid arthritis, other autoimmune diseases, orosteochondritis dessicans. In addition, cartilage damage or disruptionoccurs as a result of certain genetic or metabolic disorders, cartilagemalformation is often seen in forms of dwarfism in humans, and/orcartilage damage or disruption is often a result of reconstructivesurgery; thus compounds, compositions, and methods would be usefultherapy in these patients, whether alone or in connection with otherapproaches.

It is further contemplated that compounds, compositions, and methods ofthe present invention may be used to treat, ameliorate or preventvarious cartilagenous disorders and/or associated symptoms or effects ofsuch conditions. Exemplary conditions or disorders for treatment,amelioration and/or prevention with compounds, compositions, and methodsof the invention, include, but are not limited to systemic lupuserythematosis, rheumatoid arthritis, juvenile chronic arthritis,osteoarthritis, degenerative disc disease, spondyloarthropathies, EhlersDanlos syndrome, systemic sclerosis (scleroderma) or tendon disease.Other conditions or disorders that may benefit from treatment withcompounds for amelioration of associated effects include idiopathicinflammatory myopathies (dermatomyositis, polymyositis), Sjogren'ssyndrome, systemic vasculitis, sarcoidosis, autoimmune hemolytic anemia(immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmunethrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediatedthrombocytopenia), thyroiditis (Grave's disease, Hashimoto'sthyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis),diabetes mellitus, immune-mediated renal disease (glomerulonephritis,tubulointerstitial nephritis), demyelinating diseases of the central andperipheral nervous systems such as multiple sclerosis, idiopathicdemyelinating polyneuropathy or Guillain-Barr syndrome, and chronicinflammatory demyelinating polyneuropathy, hepatobiliary diseases suchas infectious hepatitis (hepatitis A, B, C, D, E and othernon-hepatotropic viruses), autoimmune chronic active hepatitis, primarybiliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis,inflammatory bowel disease (ulcerative colitis: Crohn's disease),gluten-sensitive enteropathy, and Whipple's disease, autoimmune orimmune-mediated skin diseases including bullous skin diseases, erythemamultiforme and contact dermatitis, psoriasis, allergic diseases such asasthma, allergic rhinitis, atopic dermatitis, food hypersensitivity andurticaria, immunologic diseases of the lung such as eosinophilicpneumonias, idiopathic pulmonary fibrosis and hypersensitivitypneumonitis, transplantation associated diseases including graftrejection and graft-versus-host-disease.

It is contemplated that compounds and/or compositions of the presentinvention can promote expression of collagen in human dermal fibroblast.Collagen is the major structural component of the dermi. Collagen isvital for skin health and has been widely used in dermal treatment ofwrinkles and skin aging, and as a healing aid for burn patients.Collagen is produced in fibroblast, and both human and bovine collagenis widely used. The invention therefore provides a method of increasingproduction of collagen in fibroblast by contacting the fibroblasts witha compound or composition of the invention, thereby increasing theproduction of collagen in the fibroblast. The contacting may be in vivoby direct injection of the compound in the areas to be treated. Thecontacting may be in vitro into a population of fibroblasts.

Pharmaceutical Compositions, Dosage and Administration

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In a further embodiment, the composition comprisesat least two pharmaceutically acceptable carriers, such as thosedescribed herein. The pharmaceutical composition can be formulated forparticular routes of administration such as oral administration,parenteral administration (e.g. by injection, infusion, transdermal ortopical administration), and rectal administration. Topicaladministration may also pertain to inhalation or intranasal application.The pharmaceutical compositions of the present invention can be made upin a solid form (including, without limitation, capsules, tablets,pills, granules, powders or suppositories), or in a liquid form(including, without limitation, solutions, suspensions or emulsions).Tablets may be either film coated or enteric coated according to methodsknown in the art. Typically, the pharmaceutical compositions are tabletsor gelatin capsules comprising the active ingredient together with oneor more of:

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and    -   e) absorbents, colorants, flavors and sweeteners.

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. In some embodiments, compounds and compositions ofthe present invention are applied by direct injection into the synovialfluid of a joint, systemic administration (oral or intravenously) ordirectly into a cartilage defect, either alone or complexed with asuitable carrier for extended release of the compound. In someembodiments, compounds or compositions are administered in abiocompatible matrix or scaffold.

Compounds, compositions, and methods of the present invention can alsobe used in conjunction with a surgical procedure at an affected joint.Administration of a compounds or composition of the invention may occurprior to, during or in conjunction with, and/or after a surgicalprocedure. For example, compounds, compositions and methods of theinvention can be used to expand chondrocyte populations in culture forautologous or allogenic chondrocyte implantation (ACI). Chondrocytes canbe optionally implanted with concurrent treatment consisting ofadministration of compounds and compositions of the present invention.In these procedures, for example, chondrocytes can be harvestedarthroscopically from an uninjured minor load-bearing area of a damagedjoint, and can be cultured in vitro, optionally in the presence ofcompounds and compositions of the present invention and/or other growthfactors to increase the number of cells prior to transplantation.Expanded cultures are then optionally admixed with compounds andcompositions of the present invention and/or placed in the joint spaceor directly into the defect. In certain embodiments, expanded cultures(optionally with compounds of the present invention) are placed in thejoint space suspended in a matrix or membrane.

In other embodiments, compounds and compositions of the presentinvention can be used in combination with one or more periosteal orperichondrial grafts that contain cartilage forming cells and/or help tohold the transplanted chondrocytes or chondrocyte precursor cells inplace. In some embodiments, compounds and compositions of the presentinvention are used to repair cartilage damage in conjunction with otherprocedures, including but not limited to lavage of a joint, stimulationof bone marrow, abrasion arthroplasty, subchondral drilling, ormicrofracture of proximal subchondral bone. Optionally, followingadministration of compounds and compositions of the present inventionand growth of cartilage, additional surgical treatment may be beneficialto suitably contour newly formed cartilage surface(s).

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents. Atherapeutic agent is, for example, a chemical compound, peptide,antibody, antibody fragment or nucleic acid, which is therapeuticallyactive or enhances the therapeutic activity when administered to apatient in combination with a compound of the invention.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of joint damageresulting from joint injury or arthritis. Products provided as acombined preparation include a composition comprising the compound offormula (I) and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and the othertherapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and a second therapeutic agent(s).The second agent may be one or more additional chondrocytedifferentiation agent. Examples of chondrocyte differentiation agentinclude but are not limited to angiopoietin-like 3 protein (ANGPTL3),insulin growth factor (IGF1), SM04690 (Wnt inhibitor), Janus kinaseinhibitors (such as Ruxolitinib, Tofacitinib, Baricitinib), oral salmoncalcitonin, SD-6010 (iNOS inhibitor), vitamin D3 (choliecalciferol),collagen hydrolyzate, bone morphogenetic protein 7 (BMP7), rusalatideacetate, avocado soy unsaponifiables (ASU), a steroid, a non-steroidalanti-inflammatory agent (NSAID), hyaluronic acid, kartogenin andTPX-100. The second agent may be a chondrocyte differentiation agenthaving Formula (I) as described in WO 2015/175487. Optionally, thepharmaceutical composition may comprise a pharmaceutically acceptablecarrier, as described above.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10-3 molar and10-9 molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

EXAMPLES

Temperatures are given in degrees Celsius. The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Unless otherwise specified, startingmaterials are generally available from commercial sources, such as butnot limited to, TCl Fine Chemical (Japan), Aurora Fine Chemicals LLC(San Diego, Calif.), FCH Group (Ukraine), Aldrich Chemicals Co.(Milwaukee, Wis.), Acros Organics (Fairlawn, N.J.), Maybridge ChemicalCompany, Ltd. (Cornwall, England), Matrix Scientific (USA), Enamine Ltd(Ukraine), Combi-Blocks, Inc. (San Diego, Calif.), Oakwood Products,Inc. (USA), Apollo Scientific, Ltd. (UK).

The Examples herein merely illuminate the invention and does not limitthe scope of the invention otherwise claimed. Further, the compounds ofthe present invention can be produced by organic synthesis methods knownto one of ordinary skill in the art as shown in the following examples.Where desired, conventional protecting groups are used to protectreactive functional groups in accordance with standard practice, forexample, see T. W. Greene and P. G. M. Wuts in “Protecting Groups inOrganic Synthesis”, John Wiley and Sons, 1991.

Abbreviations

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “aq” foraqueous, “FCC” for flash column chromatography, “eq” for equivalent orequivalents, “g” for gram or grams, “mg” for milligram or milligrams,“L” for liter or liters, “mL” for milliliter or milliliters, “μL” formicroliter or microliters, “N” for normal, “M” for molar, “nM” fornanomolar, “mol” for mole or moles, “mmol” for millimole or millimoles,“min” for minute or minutes, “h” or “hrs” for hour or hours, “RT” forroom temperature, “ON” for overnight, “atm” for atmosphere, “psi” forpounds per square inch, “conc.” for concentrate, “sat” or “sat'd” forsaturated, “MW” for molecular weight, “mw” or “pwave” for microwave,“mp” for melting point, “Wt” for weight, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” or “LC-MS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclearmagnetic resonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “b” for delta, “δ” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, “ee” for “enantiomeric excess” and “α”, “β”, “R”,“r”, “S”, “s”, “E”, and “Z” are stereochemical designations familiar toone skilled in the art.

The following abbreviations used herein below have the correspondingmeanings:

-   AcOH acetic acid-   app apparent-   ATP adenosine 5-triphosphate-   BINAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   BOC tertiary butyl carboxy-   BSA bovine serum albumin-   cProp cyclopropyl-   DAST diethylaminosulfur trifluoride-   dd doublet of doublets-   DCE dichloroethane-   DCM dichloromethane-   DIEA diethylisopropylamine-   DME 1,4-dimethoxyethane-   DMF N,N-dimethylformamide-   DMP Dess-Martin periodinane-   DMSO dimethylsulfoxide-   EDTA ethylenediamine tetraacetic acid-   ESI electrospray ionization-   Et₃N-3HF triethylamine trihydrofluoride-   EtOAc ethyl acetate-   HCl hydrochloric acid-   LiHMDS lithium bis(trimethylsilyl)amide-   MeOH methanol-   MHz megahertz-   MTBE methyl tert-butyl ether-   m/z mass to charge ratio-   NBS N-bromosuccinimide-   NMO N-methylmorpholine N-oxide-   PE petroleum ether-   ppm parts per million-   pTsOH p-toluenesulfonic acid-   rac-racemic-   Rt retention time-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   Tris-HCl aminotris(hydroxymethyl)methane hydrochloride-   XtalFluor-E (Diethylamino)difluorosulfonium tetrafluoroborate

Instrumentation LCMS Methods Employed in Characterization of Examples

Analytical LC/MS is carried out on Agilent systems using ChemStationsoftware. The system consists of:

-   -   Agilent G1312 Binary Pump    -   Agilent G1367 Well Plate Autosampler    -   Agilent G1316 Thermostated Column Compartment    -   Agilent G1315 Diode Array Detector    -   Agilent 6140/6150 Mass Spectrometer    -   SOFTA Evaporative Light Scattering Detector        Typical method conditions are as follows:    -   Flow rate: 0.9 mL/min    -   Column: 1.8 μm 2.1×50 mm Waters Acquity HSS T3 C18 column    -   Mobile Phase A: Water+0.05% TFA    -   Mobile Phase B: Acetonitrile+0.035% TFA    -   Run Time: 2.25 minutes    -   Method A: Unless otherwise stated, the system runs a gradient        from 10% B to 90% B in 1.35 minutes. A 0.6 minute wash at 100% B        follows the gradient. The remaining duration of the method        returns the system to initial conditions.    -   Method B: The system starts the gradient at 20% B rather than        10% B.    -   Method C: The system starts the gradient at 30% B rather than        10% B.    -   Method D: The system starts the gradient at 40% B rather than        10% B.    -   Typical mass spectrometer scan range is 100 to 1000 amu.

NMR Methods

Proton spectra are recorded on a Bruker AVANCE II 400 MHz with 5 mm QNPCryoprobe or a Bruker AVANCE III 500 MHz with 5 mm QNP probe unlessotherwise noted. Chemical shifts are reported in ppm relative todimethyl sulfoxide (b 2.50), chloroform (b 7.26), methanol (b 3.34),dichloromethane (b 5.32), acetone (b 2.05), or acetonitrile (b 1.94). Asmall amount of the dry sample (2-5 mg) is dissolved in an appropriatedeuterated solvent (0.6 mL).

ISCO Methods Employed in Purification of Examples

ISCO flash chromatography is performed on Teledyne COMBIFLASH® systemwith prepacked silica RediSep® column.

Preparative HPLC Methods Employed in Purification of Examples

Preparative HPLC is carried out on Waters Autoprep systems usingMassLynx and FractionLynx software. The system consists of:

-   -   Waters 2767 Autosampler/Fraction Collector    -   Waters 2525 Binary Pump    -   Waters 515 Makeup Pump    -   Waters 2487 Dual Wavelength UV Detector    -   Waters ZQ Mass Spectrometer        Typical method conditions are as follows:    -   Flow Rate: 100 mL/min    -   Column: 10 μm 19×50 mm Waters Atlantis T3 C18 column    -   Injection Volume: 0-1000 μL    -   Mobile Phase A: Water+0.05% TFA    -   Mobile Phase B: Acetonitrile+0.035% TFA    -   Run Time: 4.25 minutes

The system runs a gradient from X % B to Y % B as appropriate for theexamples in 3 minutes following a 0.25 minute hold at initialconditions. A 0.5 minute wash at 100% B follows the gradient. Theremaining duration of the method returns the system to initialconditions. Fraction collection is triggered by mass detection throughFractionLynx software.

Chiral Preparative HPLC Methods Employed in Purification of Examples

SFC chiral screening is carried out on a Thar Instruments PrepInvestigator system coupled to a Waters ZQ mass spectrometer. The TharPrep Investigator system consists of:

-   -   Leap HTC PAL autosampler    -   Thar Fluid Delivery Module (0 to 10 mL/min)    -   Thar SFC 10 position column oven    -   Waters 2996 PDA    -   Jasco CD-2095 Chiral Detector    -   Thar Automated Back Pressure Regulator

All of the Thar components are part of the SuperPure Discovery Seriesline. The system flows at 2 mL/min (4 mL/min for the WhelkO-1 column)and kept at 30° C. The system back pressure is set to 125 bar. Eachsample is screened through a battery of six 3 μm columns:

-   -   3 μm 4.6×50 mm ChiralPak AD    -   3 μm 4.6×50 mm ChiralPak OD    -   3 μm 4.6×50 mm ChiralPak OJ    -   5 μm 4.6×250 mm Whelk O-1    -   3 μm 4.6×50 mm ChiralPak AS    -   3 μm 4.6×50 mm Lux-Cellulose-2

The system runs a gradient from 5% co-solvent to 50% co-solvent in 5minutes followed by a 0.5 minute hold at 50% co-solvent, a switch backto 5% co-solvent and a 0.25 minute hold at initial conditions. Inbetween each gradient there is a 4 minute equilibration method thatflows 5% co-solvent through the next column to be screened. The typicalsolvents screened are MeOH, MeOH+20 mM NH₃, MeOH+0.5% DEA, IPA, andIPA+20 mM NH₃. Once separation is detected using one of the gradientmethods, an isocratic method can be developed, and if necessary, scaledup for purification on the Thar Prep80 system.

Intermediates

Intermediates 1c-1j were prepared following the general procedures inScheme 1.

Intermediate 1c. Methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate

Step A: To a stirring solution of methyl propiolate (200 g, 2.38 mol,198 mL) in acetone (2.50 L) was added AgNO₃ (36.4 g, 214 mmol, 36.0 mL).After 5 min, NBS (445 g, 2.50 mol) was added portionwise, and thereaction mixture was stirred at 25° C. for 12 h. The reaction mixturewas filtered, the filtrate was concentrated, and the residue wastriturated with 10% EtOAc/PE (1500 mL), and the filtrate wasconcentrated again. The residue was purified by column chromatography(0-5% EtOAc/PE) to give methyl 3-bromopropiolate (1b) as a yellow oilwhich was used for the next step directly.

Step B: A solution of methyl 3-bromopropiolate (1b, 200 g, 1.23 mol),furan (419 g, 6.15 mol, 445 mL) in toluene (2.50 L) was degassed bypassing nitrogen gas through the reaction vessel for 2 min at 0° C.,then the reaction mixture was warmed to 90° C. for 72 hour to give ablack solution. The reaction mixture was concentrated, and the residuewas purified by column chromatography (2-5% EtOAc/PE) to give methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate. Four batcheswere purified separately and combined to afford methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1c) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ=7.25-7.17 (m, 2H), 5.70 (t, J=1.6Hz, 1H), 5.33 (t, J=1.7 Hz, 1H), 3.82-3.75 (m, 3H).

Intermediate 1d. Methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate

Step C: A solution of 2,2,2-trichloroacetic acid (91.2 g, 558 mmol, 56.3mL) in 1,2-dichloroethane (300 mL) was added to a cooled solution ofdiethylzinc (1 M, 558 mL, 558 mmol) in 1,2-dichloroethane (1200 mL) at−45° C. The solution was warmed to 0° C. and was stirred for 20 min.Diiodomethane (150 g, 558 mmol, 45.0 mL) was added to the reactionmixture and it was allowed to stir at 0° C. for another 10 min. Asolution of methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1c, 60.0 g,260 mmol) in 1,2-dichloroethane (300 mL) was added to the reactionmixture which was stirred at 15° C. for 16 h. The reaction mixture wasdiluted with 1 M HCl (1200 mL) and the aqueous phase was extracted withDCM (2000 mL 2×). The combined organic layers were washed with sat. aq.NaHCO₃ (1000 mL), brine (1000 mL), dried over Na₂SO₄, filtered andconcentrated to give a yellow oil. The crude was purified by columnchromatography (0-10% EtOAc/PE) to give methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(1d) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.97-4.92 (m, 1H),4.89-4.85 (m, 1H), 3.73 (s, 3H), 1.58-1.52 (m, 2H), 1.44-1.38 (m, 1H),1.04-0.95 (m, 1H).

Intermediate 1e Methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand Methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Step D: A solution of methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1c, 130 g, 563mmol, 1.00 eq) in THF (800 mL) was treated with BH₃-THF (1 M, 563 mL,563 mmol) and was stirred at 0° C. for 2 hr. A solution of phosphatebuffer, pH=7 (1000 mL) was added dropwise, followed by a mixture of H₂O₂(270 mL, 2.81 mol, 30% v/v) and NaOH (2 M, 338 mL, 676 mmol) was addedslowly and the mixture was stirred at 0° C. for 2 hr. The reactionmixture was extracted with ethyl acetate (500 mL 3×), and the combinedorganic layers was washed with sat. aq. NaHSO₃ solution (500 mL 2×),brine (500 mL), dried (Na₂SO₄) and concentrated. The residue waspurified by column chromatography (2-50% EtOAc/PE) to give the desiredproduct. Two batches were combined to afford 1e as a 1.3:1 mixture ofalcohol regioisomers favoring the 5-hydroxy product as a yellow solid.1.3:1 mixture of alcohol regioisomers: ¹H NMR (400 MHz, CDCl₃) δ5.25-5.02 (m, 1H), 4.94-4.74 (m, 1H), 4.23-4.14 (m, 1H), 3.80-3.78 (m,3H), 2.14-2.01 (m, 1H), 1.91-1.81 (m, 1H), 1.69-1.60 (m, 1H).

Intermediate 1f Methyl(1R,4S,5S)-3-bromo-5-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand Methyl(1S,4S,6R)-3-bromo-6-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Step E: A suspension of 1e (500 mg, 2.01 mmol) and silver oxide (465 mg,2.01 mmol) in acetonitrile (5 mL) at RT was treated with iodomethane(0.125 mL, 2.01 mmol) and was warmed at 80° C. for 16 h. The reactionwas cooled to room temperature and filtered through a pad of celite. Thesolvent was concentrated and the resulting residue was purified bycolumn chromatography using hexanes and EtOAc to afford if as a mixtureof methoxy regioisomers. LC-MS: Rt=1.25 min; MS m/z [M+H]⁺ 263.0.

Intermediate 1g Methyl(1R,4S,5R)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand Methyl(1S,4S,6S)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Step F: A solution of 1e (1.00 g, 4.02 mmol) in DCM (80 mL) at RT wastreated with DAST (3.71 mL, 28.1 mmol) and was stirred for 18 h. Thereaction mixture was concentrated and was purified by FCC (0-50%EtOAc/DCM) to afford 1g as a mixture of fluorine regioisomers. LC-MS:Rt=1.15 min; MS m/z [M+H]⁺ 251.1.

Intermediate 1h Methyl3-bromo-5-oxo-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate and methyl3-bromo-6-oxo-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Step G: A solution of 1e (2.00 g, 8.03 mmol) in DCM (40 mL) at 0° C. wastreated portion-wise with Dess-Martin reagent (10.2 g, 24.1 mmol) over 5minutes. The reaction mixture was warmed to RT and was stirred for 6 h.The reaction was cooled to 0° C. and quenched with a solution ofsaturated aqueous sodium bicarbonate. The aqueous layer was washed withDCM×3. The combined organic layers were dried over anhydrous sodiumsulfate. The crude compound was purified by silica column chromatographyto afford 1h as a mixture of ketone regioisomers. LC-MS: Rt=1.10 min; MSm/z [M+H]⁺ 246.9.

Intermediate 1i Methyl(1R,4S,5R)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand Methyl(1S,4S,6S)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Step H: A solution of 1h (50.0 mg, 0.202 mmol) in THF (2 ml) at RT wastreated with NaBH₄ (15.3 mg, 0.405 mmol) and was stirred at RT for 16 h.The reaction mixture was diluted with EtOAc and sat. aq. NH₄Cl, washedwith water and brine, dried (Na₂SO₄), filtered, and concentrated toafford 1i as a mixture of alcohol regioisomers. LC-MS: Rt=0.57 min; MSm/z [M+H]⁺ 249.0.

Intermediate 1 Methyl(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand Methyl(1S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Step I: A solution of 1i (3.70 g, 14.9 mmol) in DCE (74 ml) was treatedwith triethylamine trihydrofluoride (7.26 ml, 44.6 mmol) and thenXtalFluor-E (6.83 g, 29.7 mmol) and was warmed at 80° C. for 1 h. Thereaction mixture was cooled to RT, diluted with DCM, washed with sat.aq. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated. Theresulting residue was purified by FCC to afford 1j as a mixture offluorine regioisomers. LC-MS: Rt=1.18 min; MS m/z [M+H]⁺ 251.1.

EXAMPLES

Unless otherwise stated, the examples described below consist of amixture of enantiomers; and in some examples a mixture of alcohol,fluorine, or methoxy regioisomers. In the case of a mixture ofregioisomers, the structure and name for the major regioisomer isprovided with the approximate ratio of the regioisomers.

Example 1:(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Title compound was prepared from methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) using Steps A-C as in Scheme 2.

Step A: To a stirring solution of 1d (4.70 g, 19.2 mmol) in THF (25 mL)and water (6 mL) at 0° C. was added acetic acid (4.40 mL) andportion-wise Zn (5.00 g, 77.0 mmol). The reaction slurry was stirred toroom temperature for 15 minutes. The reaction was filtered andneutralized with saturated sodium bicarbonate to pH 7. The compound wasextracted with ethyl acetate. The organic layer was washed with waterand brine and dried over anhydrous sodium sulfate. The solvent wasconcentrated and dried under vacuo. The crude compound(1S,2S,4R,5R)-methyl 8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylatewas used in the next step without further purification. LC-MS: Rt=1.16min; MS m/z [M+H]⁺ 167.1.

Step B: A mixture of (1S,2S,4R,5R)-methyl8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate (500 mg, 3.01 mmol),(2-methoxypyridin-4-yl)boronic acid (598 mg, 3.91 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (187 mg, 0.301 mmol),chloro(1,5-cyclooctadiene)rhodium(I) dimer (74.0 mg, 0.150 mmol) andpotassium carbonate (208 mg, 1.50 mmol) in dioxane (10 mL) and water(2.5 mL) was heated at 100° C. for 1 h in the microwave. The materialwas taken in celite and the solvent was concentrated. The compound waspurified by silica column chromatography afford(1S,2S,4R,5R,6S,7S)-methyl7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxylate(cis) and (1S,2S,4R,5R,6R,7S)-methyl7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxylate(trans). cis LC-MS: Rt=1.15 min; MS m/z [M+H]⁺ 276.1. trans LC-MS:Rt=1.26 min; MS m/z [M+H]⁺ 276.1.

Step C: To a stirring solution of 5,6-dichloropyridin-3-amine (68.0 mg,0.418 mmol) in anhydrous toluene (2 mL) at 0° C. under nitrogen wasadded trimethylaluminum in toluene (2 M, 0.623 mL, 1.25 mmol). After 10minutes, the ice bath was removed and the mixture was stirred at roomtemperature for 30 minutes. (1S,2S,4R,5R,6S,7S)-methyl7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxylate(115 mg, 0.418 mmol) was added as a solid and the reaction was stirredat room temperature for 1h and then heated to 80° C. overnight. Thereaction was cooled to 0° C. and quenched with methanol. The solvent wasremoved under a stream of nitrogen. The solid was taken up in methanoland filtered through a pad of celite. The solvent was concentrated thecrude compound was purified by silica column chromatography to afford(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide.LC-MS: Rt=1.38 min; MS m/z [M+H]⁺ 406.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.98 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.84 (d, J=5.3 Hz, 1H), 7.77 (d,J=2.4 Hz, 1H), 6.83 (dd, J=5.3, 1.4 Hz, 1H), 6.68 (s, 1H), 4.66 (s, 1H),4.31 (s, 1H), 3.67 (s, 3H), 3.49 (d, J=9.7 Hz, 1H), 3.30 (d, J=9.7 Hz,1H), 1.36-1.26 (m, 2H), 0.45-0.39 (m, 1H), 0.22-0.15 (m, 1H).

Example 2:rac-(1S,2S,4R,5R,6S,7S)—N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Example 2 was synthesized according to the protocol described forExample 1 using methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) and (6-methylpyridin-3-yl)boronic acid in Step B and6-methoxypyridin-3-amine in Step C. LC-MS: Rt=0.95 min; MS m/z [M+H]⁺352.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.31 (d, J=2.1 Hz, 1H),7.71-7.68 (m, 1H), 7.550 2 (dd, J=8.0, 2.3 Hz, 1H), 7.14 (dd, J=8.9, 2.7Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.62-6.57 (m, 1H), 4.62 (s, 1H), 4.24(s, 1H), 3.73 (s, 3H), 3.49 (d, J=9.6 Hz, 1H), 3.21 (d, J=9.6 Hz, 1H),2.27 (s, 3H), 1.36-1.29 (m, 1H), 1.29-1.24 (m, 1H), 0.44-0.38 (m, 1H),0.20-0.15 (m, 1H).

Examples 3 and 4 (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6S,7S)—N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6R,7R)—N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6S,7S)—N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm Cellulose-2 @ 30° C.    -   Mobile Phase: 70% CO₂/30% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.64 min. LC-MS: Rt=1.00 min; MS m/z [M+H]⁺352.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.31 (dd, J=2.4, 0.8Hz, 1H), 7.70 (dd, J=2.7, 0.7 Hz, 1H), 7.52 (dd, J=8.0, 2.3 Hz, 1H),7.14 (dd, J=8.8, 2.7 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.8,0.7 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.73 (s, 3H), 3.49 (d, J=9.6Hz, 1H), 3.21 (d, J=9.6 Hz, 1H), 2.27 (s, 3H), 1.36-1.30 (m, 1H),1.30-1.21 (m, 1H), 0.44-0.38 (m, 1H), 0.20-0.15 (m, 1H).

Peak 2: SFC Retention Time=3.30 min. LC-MS: Rt=1.00 min; MS m/z [M+H]⁺352.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.31 (dd, J=2.4, 0.8Hz, 1H), 7.70 (dd, J=2.7, 0.7 Hz, 1H), 7.52 (dd, J=8.0, 2.3 Hz, 1H),7.14 (dd, J=8.8, 2.7 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.8,0.7 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.73 (s, 3H), 3.49 (d, J=9.6Hz, 1H), 3.21 (d, J=9.6 Hz, 1H), 2.27 (s, 3H), 1.36-1.30 (m, 1H),1.30-1.21 (m, 1H), 0.44-0.38 (m, 1H), 0.20-0.15 (m, 1H).

Examples 5-13 described infra were synthesized according to the protocoldescribed for Example 1 using methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e) and various boronic acids/esters in Step B and variousanilines in Step C to give a mixture of alcohol regioisomers.

Example 5:(1R,2S,3S,4R,5S)—N-(4,5-dichloropyridin-2-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.62 min; MS m/z [M+H]⁺ 394.1.

Example 6:(1R,2S,3S,4R,5S)—N-(5-chloro-6-methylpyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.53 min; MS m/z [M+H]⁺ 374.1. ¹H NMR (500 MHz, DMSO-d₆) δ9.62 (s, 1H), 8.12 (dd, J=5.2, 0.8 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.55(d, J=2.3 Hz, 1H), 7.12 (s, 1H), 7.03 (dd, J=5.2, 1.6 Hz, 1H), 4.95-4.92(m, 1H), 4.85-4.81 (m, 1H), 4.18 (s, 1H), 4.04-4.00 (m, 1H), 3.26 (d,J=9.8 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.38 (s, 3H), 2.27 (s, 3H),2.04-1.97 (m, 1H), 1.50-1.44 (m, 1H).˜6:1 mixture of alcoholregioisomers.

Examples 7 and 8 (Corresponding to Peak 1 and Peak 2)(1R,2S,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 65% CO₂/35% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.28 min. LC-MS: Rt=0.95 min; MS m/z [M+H]⁺394.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.11 (d, J=5.2 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 7.04-7.00(m, 1H), 4.99-4.93 (m, 1H), 4.87-4.80 (m, 1H), 4.19 (s, 1H), 4.06-4.00(m, 1H), 3.30-3.25 (m, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.26 (s, 3H),2.05-1.94 (m, 1H), 1.52-1.43 (m, 1H).

Peak 2: SFC Retention Time=2.85 min. LC-MS: Rt=0.95 min; MS m/z [M+H]⁺394.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.11 (d, J=5.2 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 7.04-7.00(m, 1H), 4.99-4.93 (m, 1H), 4.87-4.80 (m, 1H), 4.19 (s, 1H), 4.06-4.00(m, 1H), 3.30-3.25 (m, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.26 (s, 3H),2.05-1.94 (m, 1H), 1.52-1.43 (m, 1H).

Example 9:(1R,2S,3S,4R,5S)-5-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.04 min; MS m/z [M+H]⁺ 393.2. ¹H NMR (400 MHz, DMSO-d₆) δ9.64 (s, 1H), 8.10-8.07 (m, 1H), 7.46 (s, 1H), 7.38-7.33 (m, 1H),7.28-7.22 (m, 2H), 7.12 (s, 1H), 7.03 (dd, J=5.2, 1.7 Hz, 1H), 4.99-4.92(m, 1H), 4.88-4.82 (m, 1H), 4.17 (s, 1H), 4.05-3.99 (m, 1H), 3.27 (d,J=9.8 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.23 (s, 3H), 2.05-1.96 (m, 1H),1.51-1.43 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 10:(1S,2S,3S,4S,6R)-6-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.00 min; MS m/z [M+H]⁺ 393.2. ¹H NMR (400 MHz, DMSO-d₆) δ9.75 (s, 1H), 8.09 (dd, J=5.2, 0.8 Hz, 1H), 7.46 (s, 1H), 7.39-7.34 (m,1H), 7.30-7.23 (m, 2H), 7.13 (s, 1H), 7.06 (dd, J=5.2, 1.6 Hz, 1H),4.97-4.91 (m, 1H), 4.59 (s, 1H), 4.51-4.47 (m, 1H), 4.01-3.95 (m, 1H),3.24 (d, J=9.7 Hz, 1H), 3.05 (d, J=9.7 Hz, 1H), 2.22 (s, 3H), 2.05-1.97(m, 1H), 1.53-1.45 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 11:rac-(1R,2S,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.92 min; MS m/z [M+H]⁺ 381.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.96 (s, 1H), 8.30-8.27 (m, 2H), 8.00 (d, J=2.4 Hz, 1H), 7.80 (d, J=2.4Hz, 1H), 7.28-7.23 (m, 2H), 4.98-4.95 (m, 1H), 4.87-4.83 (m, 1H), 4.21(s, 1H), 4.07-4.02 (m, 1H), 3.36-3.29 (m, 1H), 3.09 (d, J=9.8 Hz, 1H),2.06-1.98 (m, 1H), 1.52-1.44 (m, 1H). ˜3:1 mixture of alcoholregioisomers.

Example 11a: (Corresponding to Peak 1)(1R,2S,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 10) by Supercritical Fluid Chromatography using the followingconditions afforded the compound listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 65% CO₂/35% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.74 min. LC-MS: Rt=0.92 min; MS m/z [M+H]⁺381.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.30-8.26 (m, 2H), 7.99(d, J=2.3 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.26-7.22 (m, 2H), 4.97 (s,1H), 4.88-4.82 (m, 1H), 4.20 (s, 1H), 4.07-4.00 (m, 1H), 3.36-3.31 (m,1H), 3.09 (d, J=9.8 Hz, 1H), 2.06-1.98 (m, 1H), 1.53-1.43 (m, 1H).

Example 12:rac-(1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.96 min; MS m/z [M+H]⁺ 379.2. ¹H NMR (400 MHz, DMSO-d₆) δ9.70 (s, 1H), 8.27-8.24 (m, 2H), 7.47 (s, 1H), 7.37-7.31 (m, 1H),7.27-7.22 (m, 4H), 4.99-4.93 (m, 1H), 4.90-4.83 (m, 1H), 4.18 (s, 1H),4.06-4.01 (m, 1H), 3.34-3.31 (m, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.07-1.95(m, 1H), 1.52-1.41 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 12a: (Corresponding to Peak 1)(1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 11) by Supercritical Fluid Chromatography using the followingconditions afforded the compound listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 95-50% CO₂/5-50% MeOH+0.5% isopropylamine in 5        minutes    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.59 min. LC-MS: Rt=0.96 min; MS m/z [M+H]⁺379.2. ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 8.27-8.24 (m, 2H), 7.47(s, 1H), 7.37-7.31 (m, 1H), 7.27-7.22 (m, 4H), 4.99-4.93 (m, 1H),4.90-4.83 (m, 1H), 4.18 (s, 1H), 4.06-4.01 (m, 1H), 3.34-3.31 (m, 1H),3.07 (d, J=9.8 Hz, 1H), 2.07-1.95 (m, 1H), 1.52-1.41 (m, 1H).

Example 13:(1S,2S,3S,4S,6R)-6-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.84 min; MS m/z [M+H]⁺ 379.2. ¹H NMR (400 MHz, DMSO-d₆) δ9.79 (s, 1H), 8.26-8.24 (m, 2H), 7.47 (s, 1H), 7.38-7.33 (m, 1H),7.29-7.23 (m, 4H), 4.97-4.93 (m, 1H), 4.60 (s, 1H), 4.52-4.49 (m, 1H),4.02-3.96 (m, 1H), 3.32-3.29 (m, 1H), 3.07 (d, J=9.6 Hz, 1H), 2.05-1.99(m, 1H), 1.55-1.47 (m, 1H). >20:1 mixture of alcohol regioisomers.

Examples 14-16 described infra were synthesized according to theprotocol described for Example 1 using methyl(1R,4S,5R)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6S)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1g) and various boronic acids/esters in Step B and variousanilines in Step C.

Example 14:(1R,2S,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.16 min; MS m/z [M+H]⁺ 395.2. Mixture of fluorineregioisomers.

Example 15:(1R,2S,3S,4R,5R)-5-fluoro-N-(6-methoxypyridin-3-yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.42 min; MS m/z [M+H]⁺ 358.2. ¹H NMR (400 MHz, DMSO-d₆) δ9.48 (s, 1H), 8.18 (dd, J=5.1, 0.8 Hz, 1H), 7.77-7.73 (m, 1H), 7.26 (dd,J=8.8, 2.7 Hz, 1H), 7.18 (s, 1H), 7.12-7.09 (m, 1H), 6.62 (dd, J=8.8,0.7 Hz, 1H), 5.29-5.08 (m, 1H), 4.90-4.84 (m, 1H), 4.69-4.63 (m, 1H),3.94-3.89 (m, 1H), 3.74 (s, 3H), 3.40-3.35 (m, 1H), 2.29 (s, 3H),2.27-2.13 (m, 1H), 1.72-1.58 (m, 1H). >20:1 mixture of fluorineregioisomers.

Example 16:(1R,2S,3S,4R,5R)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.14 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz, DMSO-d₆) δ9.80 (s, 1H), 8.11 (dd, J=5.1, 0.8 Hz, 1H), 7.48 (s, 1H), 7.40-7.34 (m,1H), 7.30-7.24 (m, 2H), 7.18 (d, J=1.6 Hz, 1H), 7.10-7.06 (m, 1H),5.29-5.08 (m, 1H), 4.91-4.87 (m, 1H), 4.70-4.64 (m, 1H), 3.97-3.90 (m,1H), 3.44-3.38 (m, 1H), 2.28-2.18 (m, 1H), 2.23 (s, 3H), 1.71-1.59 (m,1H). >20:1 mixture of fluorine regioisomers.

Examples 17-23 described infra were synthesized according to theprotocol described for Example 1 using methyl(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1j) and various boronic acids/esters in Step B and variousanilines in Step C.

Example 17:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.19 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (500 MHz, DMSO-d6) δ9.60 (s, 1H), 8.13 (dd, J=5.2, 0.7 Hz, 1H), 7.40-7.35 (m, 2H), 7.11 (s,1H), 7.02 (dd, J=5.3, 1.6 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H),5.24-5.08 (m, 1H), 4.97-4.92 (m, 1H), 4.63-4.55 (m, 1H), 3.34-3.27 (m,1H), 3.05 (d, J=9.9 Hz, 1H), 2.27 (s, 3H), 2.21-2.11 (m, 1H), 1.85-1.70(m, 1H). >20:1 mixture of fluorine regioisomers.

Example 18:(1R,2S,3S,4R,5S)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.15 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.15 (dd, J=5.2, 0.8 Hz, 1H), 8.06 (s, 1H), 7.43 (s,1H), 7.32 (dd, J=7.9, 0.8 Hz, 1H), 7.28-7.24 (m, 2H), 7.15 (s, 1H), 7.05(dd, J=5.2, 1.7 Hz, 1H), 5.15-4.98 (m, 1H), 5.06-5.02 (m, 1H), 4.74-4.68(m, 1H), 3.36-3.30 (m, 1H), 3.07-3.02 (m, 1H), 2.29 (s, 3H), 2.24-2.16(m, 1H), 1.93-1.79 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 19:(1R,2S,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.06 min; MS m/z [M+H]⁺ 396.1. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.20-8.14 (m, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.75 (d,J=2.4 Hz, 1H), 7.12 (s, 1H), 7.04 (dd, J=5.2, 1.7 Hz, 1H), 5.14-4.97 (m,1H), 5.03-5.01 (m, 1H), 4.73-4.68 (m, 1H), 3.33 (d, J=9.7 Hz, 1H), 3.07(d, J=9.7 Hz, 1H), 2.32 (s, 3H), 2.24-2.13 (m, 1H), 1.93-1.79 (m,1H). >20:1 mixture of fluorine regioisomers.

Example 20:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.36 min; MS m/z [M+H]⁺ 411.2. ¹H NMR (500 MHz, DMSO-d₆) δ9.61 (s, 1H), 7.85 (dd, J=5.3, 0.7 Hz, 1H), 7.40-7.36 (m, 2H), 7.00 (dd,J=8.8, 2.5 Hz, 1H), 6.83 (dd, J=5.3, 1.5 Hz, 1H), 6.68 (s, 1H),5.23-5.08 (m, 1H), 4.97-4.90 (m, 1H), 4.61-4.55 (m, 1H), 3.69 (s, 3H),3.32 (d, J=9.9 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.21-2.11 (m, 1H),1.83-1.70 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 21:(1R,2S,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-fluoro-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.14 min; MS m/z [M+H]⁺ 397.1. ¹H NMR (400 MHz, DMSO-d6) δ9.80 (s, 1H), 8.05 (s, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.42 (d, J=8.8 Hz,1H), 7.08 (dd, J=8.8, 2.5 Hz, 1H), 6.32 (s, 2H), 5.23-5.05 (m, 1H),4.91-4.87 (m, 1H), 4.58-4.52 (m, 1H), 3.19 (d, J=9.6 Hz, 1H), 2.94 (d,J=9.7 Hz, 1H), 2.20-2.09 (m, 1H), 1.81-1.63 (m, 1H). >20:1 mixture offluorine regioisomers.

Example 22:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.23 min; MS m/z [M+H]⁺ 395.1. ¹H NMR (500 MHz, DMSO-d₆) δ9.63 (s, 1H), 8.29 (dd, J=2.3, 0.8 Hz, 1H), 7.50 (dd, J=8.0, 2.4 Hz,1H), 7.38 (d, J=8.7 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.99 (d, J=8.0 Hz,1H), 6.94 (dd, J=8.8, 2.4 Hz, 1H), 5.26-5.10 (m, 1H), 4.96-4.89 (m, 1H),4.58-4.53 (m, 1H), 3.36 (d, J=9.7 Hz, 1H), 3.01 (d, J=9.8 Hz, 1H), 2.25(s, 3H), 2.21-2.11 (m, 1H), 1.83-1.69 (m, 1H). >20:1 mixture of fluorineregioisomers.

Example 23:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.40 min; MS m/z [M+H]⁺ 399.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.80 (s, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.40 (d,J=8.8 Hz, 1H), 7.21-7.17 (m, 1H), 7.02 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (s,1H), 5.25-5.07 (m, 1H), 4.97-4.94 (m, 1H), 4.69-4.64 (m, 1H), 3.47 (d,J=9.8 Hz, 1H), 3.11 (d, J=9.8 Hz, 1H), 2.24-2.13 (m, 1H), 1.86-1.70 (m,1H). >20:1 mixture of fluorine regioisomers.

Example 24:rac-(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Title compound was prepared from methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) using Steps A-C as in Scheme 3.

Step A: To a stirring solution of 3,4-dichloroaniline (568 mg, 3.51mmol) in anhydrous toluene (10 mL) at 0° C. under nitrogen was addedtrimethylaluminum in toluene (2 M, 3.90 mL, 7.79 mmol). After 10minutes, the ice bath was removed and the mixture was stirred at roomtemperature for 30 minutes. The reaction was cooled back to 0° C. and 1d(955 mg, 3.90 mmol, dissolved in 2 mL of toluene) was added and thereaction was stirred at room temperature for 6 h. The reaction wascooled to 0° C. and quenched with a solution of saturated aqueous NH₄Cland methanol. The suspension was filtered and the solid was washed withEtOAc. The organic layer was separated and washed with brine and driedover anhydrous sodium sulfate and concentrated. The crude compound waspurified by silica column chromatography using DCM and EtOAc to afford(1S,2S,4R,5R)-7-bromo-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide.LC-MS: Rt=1.63 min; MS m/z [M+H]⁺ 373.9. ¹H NMR (400 MHz, DMSO-d₆) δ10.10 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.65 (dd, J=8.9, 2.3 Hz, 1H),7.60 (d, J=8.8 Hz, 1H), 5.15 (s, 1H), 4.87 (s, 1H), 1.70-1.66 (m, 1H),1.60-1.55 (m, 1H), 1.42-1.39 (m, 1H), 1.02-0.98 (m, 1H).

Step B: To a stirring solution of(1S,2S,4R,5R)-7-bromo-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide(525 mg, 1.40 mmol) in THF (10 mL) and water (2.5 mL) at 0° C. was addedacetic acid (0.321 mL) and portion-wise Zn (366 mg, 5.60 mmol). Thereaction slurry was stirred to room temperature for 15 minutes. Thereaction was filtered and neutralized with saturated sodium bicarbonateto pH ˜7. The compound was extracted with ethyl acetate. The organiclayer was washed with water and brine and dried over anhydrous sodiumsulfate and concentrated. The crude compound was purified by silicacolumn chromatography (hexanes:EtOAc) to afford(1S,2S,4R,5R)—N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide.LC-MS: Rt=1.54 min; MS m/z [M+H]⁺ 296.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.11 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.9, 2.4 Hz, 1H),7.59 (d, J=8.8 Hz, 1H), 7.37 (d, J=1.7 Hz, 1H), 4.98 (s, 1H), 4.89 (d,J=1.7 Hz, 1H), 1.42-1.36 (m, 3H), 0.96-0.90 (m, 1H).

Step C: A mixture of(1S,2S,4R,5R)—N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide(150 mg, 0.507 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (133mg, 0.608 mmol), 2,2-bis(diphenylphosphino)-1,1-binapthalene (32 mg,0.051 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (12 mg, 0.025mmol) and potassium carbonate (35 mg, 0.253 mmol) in 1,4-dioxane (2 mL)and water (0.5 mL) was heated in the microwave at 100° C. for 1 h. Thecrude reaction was taken in celite and the solvent was concentrated todryness. The crude compound was purified by silica column chromatographyusing DCM and EtOAc to afford(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 23) and(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(trans). LC-MS: Rt=1.29 min; MS m/z [M+H]+ 389.0. ¹H NMR (400 MHz,DMSO-d₆) δ 9.70 (s, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.40-7.37 (m, 2H),7.16-7.13 (m, 1H), 7.06 (dd, J=5.3, 1.6 Hz, 1H), 6.99 (dd, J=8.8, 2.4Hz, 1H), 4.65 (s, 1H), 4.30 (s, 1H), 3.48 (d, J=9.7 Hz, 1H), 3.28 (d,J=9.7 Hz, 1H), 2.28 (s, 3H), 1.35-1.23 (m, 2H), 0.44-0.39 (m, 1H),0.22-0.15 (m, 1H).

Examples 24a and 24b (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxamideor(1R,2R,4S,5S,6R,7R)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 23) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.80 min. Method B LC-MS: Rt=1.06 min; MS m/z[M+H]+ 388.9. ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 8.11 (d, J=5.1Hz, 1H), 7.39 (s, 1H), 7.38 (d, J=6.6 Hz, 1H), 7.11 (s, 1H), 7.03-6.97(m, 2H), 4.65 (s, 1H), 4.29 (s, 1H), 3.46 (d, J=9.7 Hz, 1H), 3.26 (d,J=9.7 Hz, 1H), 2.26 (s, 3H), 1.35-1.25 (m, 2H), 0.43-0.39 (m, 1H),0.22-0.16 (m, 1H).

Peak 2: SFC Retention Time=3.26 min. Method B LC-MS: Rt=1.06 min; MS m/z[M+H]+ 388.9. ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 8.11 (d, J=5.1Hz, 1H), 7.39 (s, 1H), 7.38 (d, J=6.6 Hz, 1H), 7.11 (s, 1H), 7.03-6.97(m, 2H), 4.65 (s, 1H), 4.29 (s, 1H), 3.46 (d, J=9.7 Hz, 1H), 3.26 (d,J=9.7 Hz, 1H), 2.26 (s, 3H), 1.35-1.25 (m, 2H), 0.43-0.39 (m, 1H),0.22-0.16 (m, 1H).

Examples 25-46 described infra were synthesized according to theprotocol described for Example 23 using methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) and various anilines in Step A and various boronicesters/acids in Step C.

Example 25:(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.40 min; MS m/z [M+H]⁺ 405.0. ¹H NMR (400 MHz,DMSO-d₆) δ 9.72 (s, 1H), 7.83 (dd, J=5.3, 0.6 Hz, 1H), 7.39 (d, J=5.1Hz, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.01 (dd, J=8.8, 2.4 Hz, 1H), 6.83 (dd,J=5.4, 1.4 Hz, 1H), 6.69-6.66 (m, 1H), 4.65 (s, 1H), 4.28 (s, 1H), 3.68(s, 3H), 3.47 (d, J=9.7 Hz, 1H), 3.26 (d, J=9.7 Hz, 1H), 1.35-1.29 (m,1H), 1.29-1.24 (m, 1H), 0.44-0.38 (m, 1H), 0.21-0.14 (m, 1H).

Example 26:(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-fluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.63 min; MS m/z [M+H]⁺ 393.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.83 (s, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.40 (d,J=8.8 Hz, 1H), 7.19 (d, J=5.0 Hz, 1H), 7.02 (dd, J=8.9, 2.5 Hz, 1H),6.95 (s, 1H), 4.67 (d, J=2.7 Hz, 1H), 4.35 (d, J=2.7 Hz, 1H), 3.61 (d,J=9.6 Hz, 1H), 3.31 (d, J=9.6 Hz, 1H), 1.36-1.25 (m, 2H), 0.44-0.39 (m,1H), 0.23-0.18 (m, 1H).

Example 27:(1S,2S,4R,5R,6S,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.29 min; MS m/z [M+H]⁺ 389.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.73 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.46 (s, 1H), 7.36 (t, J=7.9 Hz,1H), 7.26 (t, J=9.2 Hz, 2H), 7.12 (s, 1H), 7.03 (dd, J=5.1, 1.2 Hz, 1H),4.66 (s, 1H), 4.29 (s, 1H), 3.47 (d, J=9.7 Hz, 1H), 3.29 (d, J=9.7 Hz,1H), 2.23 (s, 3H), 1.35-1.26 (m, 2H), 0.44-0.41 (m, 1H), 0.21-0.16 (m,1H).

Examples 28 and 29 (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6R,7R)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IB @ 30° C.    -   Mobile Phase: 75% CO₂/25% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.28 min. Method C LC-MS: Rt=1.03 min; MS m/z[M+H]⁺ 375.8. ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 8.82 (s, 1H),8.61 (s, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.01-6.98 (m, 1H), 4.66 (s, 1H),4.41 (s, 1H), 3.57 (d, J=9.5 Hz, 1H), 3.29 (d, J=9.7 Hz, 1H), 1.38-1.27(m, 2H), 0.45-0.40 (m, 1H), 0.24-0.18 (m, 1H).

Peak 2: SFC Retention Time=2.76 min. Method C LC-MS: Rt=1.03 min; MS m/z[M+H]⁺ 375.9. ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 8.82 (s, 1H),8.61 (s, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.01-6.98 (m, 1H), 4.66 (s, 1H),4.41 (s, 1H), 3.57 (d, J=9.5 Hz, 1H), 3.29 (d, J=9.7 Hz, 1H), 1.38-1.27(m, 2H), 0.45-0.40 (m, 1H), 0.24-0.18 (m, 1H).

Examples 30 and 31 (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6R,7R)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IA @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.63 min. Method D LC-MS: Rt=1.23 min; MS m/z[M+H]⁺ 410.8. ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 7.84 (dd,J=5.2, 0.9 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.43 (d, J=4.6 Hz, 1H), 7.31(t, J=4.9 Hz, 1H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 4.67 (s, 1H), 4.44 (s,1H), 3.89 (d, J=9.6 Hz, 1H), 3.36 (d, J=9.6 Hz, 1H), 1.42-1.37 (m, 1H),1.34-1.28 (m, 1H), 0.46-0.40 (m, 1H), 0.24-0.19 (m, 1H).

Peak 2: SFC Retention Time=3.19 min. Method D LC-MS: Rt=1.23 min; MS m/z[M+H]⁺ 410.8. ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 7.84 (dd,J=5.2, 0.9 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.43 (d, J=4.6 Hz, 1H), 7.31(t, J=4.9 Hz, 1H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 4.67 (s, 1H), 4.44 (s,1H), 3.89 (d, J=9.6 Hz, 1H), 3.36 (d, J=9.6 Hz, 1H), 1.42-1.37 (m, 1H),1.34-1.28 (m, 1H), 0.46-0.40 (m, 1H), 0.24-0.19 (m, 1H).

Example 32:(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method C LC-MS: Rt=1.29 min; MS m/z [M+H]⁺ 411.8. ¹H NMR (400 MHz,DMSO-d₆) δ 10.34 (s, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.84 (d, J=2.4 Hz,2H), 7.31 (t, J=4.9 Hz, 1H), 4.70 (s, 1H), 4.44 (s, 1H), 3.90 (d, J=9.6Hz, 1H), 3.39 (d, J=9.6 Hz, 1H), 1.43-1.37 (m, 1H), 1.33-1.28 (m, 1H),0.46-0.40 (m, 1H), 0.25-0.19 (m, 1H).

Example 33:(1S,2S,4R,5R,6S,7S)—N-(6-methoxypyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=0.92 min; MS m/z [M+H]⁺ 338.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.63 (s, 1H), 8.62 (d, J=5.9 Hz, 2H), 7.76 (dd, J=2.7, 0.7 Hz, 1H), 7.73(d, J=5.9 Hz, 2H), 7.31 (dd, J=8.9, 2.7 Hz, 1H), 6.62 (dd, J=8.8, 0.7Hz, 1H), 4.71 (s, 1H), 4.40 (s, 1H), 3.75 (dt, J=9.6, 0.6 Hz, 1H), 3.73(s, 3H), 3.39 (d, J=9.6 Hz, 1H), 1.40-1.29 (m, 2H), 0.47-0.41 (m, 1H),0.25-0.18 (m, 1H).

Example 34:(1S,2S,4R,5R,6S,7S)-7-(2,3-difluoropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method C LC-MS: Rt=0.89 min; MS m/z [M+H]⁺ 373.9. ¹H NMR (400 MHz,DMSO-d6) δ 9.70 (s, 1H), 7.85 (d, J=5.2 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H),7.33 (t, J=4.9 Hz, 1H), 7.28 (dd, J=8.9, 2.7 Hz, 1H), 6.65 (dd, J=8.9,0.7 Hz, 1H), 4.67 (s, 1H), 4.42 (s, 1H), 3.88 (d, J=9.6 Hz, 1H), 3.74(s, 3H), 3.35 (d, J=9.6 Hz, 1H), 1.42-1.37 (m, 1H), 1.34-1.29 (m, 1H),0.46-0.40 (m, 1H), 0.23-0.16 (m, 1H).

Example 35:(1S,2S,4R,5R,6S,7S)—N-(6-methoxypyridin-3-yl)-7-(6-(trifluoromethyl)pyridin-2-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.47 min; MS m/z [M+H]⁺ 406.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.63 (s, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.63 (d,J=8.0 Hz, 1H), 7.60-7.57 (m, 1H), 7.27 (dd, J=8.9, 2.7 Hz, 1H), 6.59 (d,J=8.9 Hz, 1H), 4.66 (s, 1H), 4.48 (s, 1H), 3.78 (d, J=9.7 Hz, 1H), 3.72(s, 3H), 3.36 (d, J=9.7 Hz, 1H), 1.42-1.36 (m, 1H), 1.31-1.26 (m, 1H),0.46-0.41 (m, 1H), 0.23-0.18 (m, 1H).

Example 36:(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-fluoropyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.50 min; MS m/z [M+H]⁺ 394.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.03 (s, 1H), 8.57 (d, J=1.5 Hz, 2H), 7.43 (d, J=6.1 Hz,1H), 7.42 (s, 1H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 4.66 (s, 1H), 4.42 (s,1H), 3.66 (d, J=9.5 Hz, 1H), 3.29 (d, J=9.5 Hz, 1H), 1.37-1.26 (m, 2H),0.46-0.40 (m, 1H), 0.25-0.17 (m, 1H).

Example 37:(1S,2S,4R,5R,6S,7S)-7-(pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0²4]octane-6-carboxamide

LC-MS: Rt=1.41 min; MS m/z [M+H]⁺ 376.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.96 (s, 1H), 8.79 (s, 1H), 8.63 (s, 2H), 7.44 (s, 1H), 7.38 (t, J=8.0Hz, 1H), 7.29-7.24 (m, 2H), 4.68 (s, 1H), 4.41 (s, 1H), 3.59 (d, J=9.6Hz, 1H), 3.30 (s, 1H), 1.40-1.35 (m, 1H), 1.34-1.28 (m, 1H), 0.46-0.41(m, 1H), 0.23-0.18 (m, 1H).

Example 38:(1S,2S,4R,5R,6S,7S)-7-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.28 min; MS m/z [M+H]⁺ 375.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.79 (s, 1H), 8.28 (d, J=6.0 Hz, 2H), 7.48 (s, 1H), 7.36 (t, J=7.9 Hz,1H), 7.29 (dd, J=4.6, 1.4 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 4.68 (s, 1H),4.31 (s, 1H), 3.54 (d, J=9.7 Hz, 1H), 3.31 (d, J=9.7 Hz, 1H), 1.37-1.32(m, 1H), 1.31-1.26 (m, 1H), 0.46-0.40 (m, 1H), 0.22-0.16 (m, 1H).

Example 39:(1S,2S,4R,5R,6S,7S)-7-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.24 min; MS m/z [M+H]⁺ 391.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.85 (s, 1H), 8.05 (s, 2H), 7.51 (d, J=2.4 Hz, 1H), 7.42 (d, J=8.8 Hz,1H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 6.27 (s, 2H), 4.59 (s, 1H), 4.23 (s,1H), 3.33 (d, J=9.3 Hz, 1H), 3.15 (d, J=9.5 Hz, 1H), 1.32-1.26 (m, 1H),1.26-1.20 (m, 1H), 0.42-0.37 (m, 1H), 0.20-0.15 (m, 1H).

Example 40:(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-morpholinopyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.55 min; MS m/z [M+H]⁺ 461.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.84 (s, 1H), 8.18 (s, 2H), 7.43-7.39 (m, 2H), 7.04 (dd, J=8.8, 2.4 Hz,1H), 4.60 (s, 1H), 4.28 (s, 1H), 3.48 (s, 8H), 3.39 (d, J=9.4 Hz, 1H),3.18 (d, J=9.5 Hz, 1H), 1.34-1.28 (m, 1H), 1.28-1.23 (m, 1H), 0.44-0.38(m, 1H), 0.21-0.14 (m, 1H).

Example 41:(1S,2S,4R,5R,6S,7S)-7-(2-fluoropyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.58 min; MS m/z [M+H]⁺ 393.1. ¹H NMR (400 MHz, DMSO-d₆) δ9.84 (s, 1H), 7.92 (d, J=5.2 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.38 (t,J=7.9 Hz, 1H), 7.31-7.24 (m, 2H), 7.24-7.18 (m, 1H), 6.96 (d, J=1.4 Hz,1H), 4.69 (s, 1H), 4.35 (s, 1H), 3.62 (d, J=9.6 Hz, 1H), 3.33 (d, J=9.6Hz, 1H), 1.39-1.27 (m, 2H), 0.46-0.40 (m, 1H), 0.23-0.17 (m, 1H).

Example 42:(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.35 min; MS m/z [M+H]⁺ 390.0. ¹H NMR (400 MHz,DMSO-d₆) δ 9.92 (s, 1H), 8.48 (s, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.30 (d,J=2.4 Hz, 1H), 6.98 (dd, J=8.8, 2.4 Hz, 1H), 4.64 (s, 1H), 4.36 (s, 1H),3.53 (d, J=9.5 Hz, 1H), 3.25 (d, J=9.6 Hz, 1H), 2.38 (s, 3H), 1.37-1.31(m, 1H), 1.30-1.25 (m, 1H), 0.46-0.40 (m, 1H), 0.23-0.17 (m, 1H).

Example 43:rac-(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.17 min; MS m/z [M+H]⁺ 376.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.17 (s, 1H), 8.50-8.42 (m, 2H), 8.03 (d, J=2.4 Hz, 1H), 7.85 (d, J=2.4Hz, 1H), 7.54-7.49 (m, 2H), 4.70 (s, 1H), 4.39 (s, 1H), 3.68 (d, J=9.6Hz, 1H), 3.40 (d, J=9.7 Hz, 1H), 1.41-1.29 (m, 2H), 0.46-0.42 (m, 1H),0.26-0.18 (m, 1H).

Examples 43a and 43b (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6R,7R)—N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 43) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 30×250 mm IC @ 30° C.    -   Mobile Phase: 65% CO₂/35% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.64 min. LC-MS: Rt=1.17 min; MS m/z [M+H]⁺376.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.50-8.42 (m, 2H),8.03 (d, J=2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.54-7.49 (m, 2H), 4.70(s, 1H), 4.39 (s, 1H), 3.68 (d, J=9.6 Hz, 1H), 3.40 (d, J=9.7 Hz, 1H),1.41-1.29 (m, 2H), 0.46-0.42 (m, 1H), 0.26-0.18 (m, 1H).

Peak 2: SFC Retention Time=2.80 min. LC-MS: Rt=1.17 min; MS m/z [M+H]⁺376.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.50-8.42 (m, 2H),8.03 (d, J=2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.54-7.49 (m, 2H), 4.70(s, 1H), 4.39 (s, 1H), 3.68 (d, J=9.6 Hz, 1H), 3.40 (d, J=9.7 Hz, 1H),1.41-1.29 (m, 2H), 0.46-0.42 (m, 1H), 0.26-0.18 (m, 1H).

Example 44:(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.27 min; MS m/z [M+H]⁺ 375.0. ¹H NMR (500 MHz, DMSO-d₆) δ9.73 (s, 1H), 8.29-8.25 (m, 2H), 7.41-7.32 (m, 2H), 7.26-7.21 (m, 2H),7.01-6.96 (m, 1H), 4.69-4.62 (m, 1H), 4.33-4.27 (m, 1H), 3.53-3.48 (m,1H), 3.30-3.25 (m, 1H), 1.37-1.31 (m, 1H), 1.31-1.25 (m, 1H), 0.45-0.38(m, 1H), 0.24-0.17 (m, 1H).

Examples 45 and 46 (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6R,7R)—N-(5,6-dichloropyridin-3-yl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6S,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 70% CO₂/30% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.50 min. LC-MS: Rt=1.19 min; MS m/z [M+H]⁺390.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.11 (d, J=5.2 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 7.01 (dd,J=5.1, 1.3 Hz, 1H), 4.66 (s, 1H), 4.32 (s, 1H), 3.48 (d, J=9.7 Hz, 1H),3.31 (d, J=10.1 Hz, 1H), 2.25 (s, 3H), 1.36-1.26 (m, 2H), 0.45-0.39 (m,1H), 0.22-0.16 (m, 1H).

Peak 2: SFC Retention Time=2.54 min. LC-MS: Rt=1.19 min; MS m/z [M+H]⁺390.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.11 (d, J=5.2 Hz, 1H),8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 7.01 (dd,J=5.1, 1.3 Hz, 1H), 4.66 (s, 1H), 4.32 (s, 1H), 3.48 (d, J=9.7 Hz, 1H),3.31 (d, J=10.1 Hz, 1H), 2.25 (s, 3H), 1.36-1.26 (m, 2H), 0.45-0.39 (m,1H), 0.22-0.16 (m, 1H).

Example 47:rac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e) using Steps A-C as in Scheme 3.

Step A: To a stirring solution of 3,4-dichloroaniline (44.0 g, 271 mmol)in anhydrous toluene (100 mL) at 0° C. under nitrogen was addedtrimethylaluminum in toluene (2 M, 313 mL, 626 mmol). After 10 minutes,the ice bath was removed and the mixture was stirred at RT for 30minutes. The reaction was cooled back to 0° C. and the mixture of methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e, 26.0 g, 104 mmol) in 600 mL of toluene was added andthe reaction was stirred ar RT for 6 h. The reaction was cooled to 0° C.and was slowly quenched with saturated aqueous ammonium chloride (500ml). The suspension was filtered and the solid was washed with EtOAc(500 mL 3×) and methanol (100 mL 2×). The combined organic layer waswashed with sat. aq. NH₄Cl (300 mL), water (300 mL), brine (300 mL) anddried over anhydrous sodium sulfate. The crude compound was purified bysilica column chromatography using PE and EtOAc to give the mixture of(1R,4S,5S)-3-bromo-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamideand(1S,4S,6R)-3-bromo-N-(3,4-dichlorophenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamideas a 2:1 mixture of alcohol regioisomers favoring the 5-hydroxy productas a light-yellow solid. ¹H NMR (400 MHz, CDCl₃) b ppm 7.99-7.95 (m,1H), 7.79-7.78 (m, 1H), 7.43-7.38 (m, 2H), 5.38-5.36 (m, 0.7H),5.18-5.17 (m, 0.3H), 5.02-5.01 (m, 0.3H), 4.88-4.86 (m, 0.7H), 4.29-4.24(m, 1H), 2.22-2.19 (m, 0.7H), 2.15-2.08 (m, 0.3H), 1.74-1.69 (m, 1H),0.89-0.85 (m, 1H).

Step B: To a stirring solution of a mixture of(1R,4S,5S)-3-bromo-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamideand(1S,4S,6R)-3-bromo-N-(3,4-dichlorophenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide(14.5 g, 38.3 mmol) in THF (240 mL) and H₂O (60 mL) at 0° C. was addedAcOH (18.0 mL) and Zn powder (20.0 g, 306 mmol). The reaction slurry wasstirred at RT for 2 h. The reaction was filtered and neutralized withsaturated aqueous sodium bicarbonate to pH 7. The compound was extractedwith ethyl acetate (200 mL 3×). The organic layer was washed with water(200 mL), brine (100 mL) and dried over anhydrous sodium sulfate andconcentrated. The resulting solid was triturated with MTBE (30 mL), thenfiltered to collect the solid to give a regioisomeric mixture of(1R,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamideand(1S,4S,6R)—N-(3,4-dichlorophenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamideas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.03-8.02(d, 1H), 7.64-7.57 (m, 2H), 7.09-7.07 (d, 1H), 5.15-5.08 (m, 2H),4.87-4.81 (m, 1H), 3.91-3.89 (m, 1H), 1.76-1.72 (m, 1H), 1.44-1.40 (m,1H).

Step C: A mixture of(1R,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamideand(1S,4S,6R)—N-(3,4-dichlorophenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide(250 mg, 0.833 mmol), pyridin-4-ylboronic acid (133 mg, 1.08 mmol),2,2-bis(diphenylphosphino)-1,1-binapthalene (52 mg, 0.083 mmol),chloro(1,5-cyclooctadiene)rhodium(I) dimer (21 mg, 0.042 mmol) andpotassium carbonate (58.0 mg, 0.416 mmol) in 1,4-dioxane (6 mL) andwater (1.5 mL) was heated at 100° C. for 1 h in the microwave. Thereaction mixture was concentrated onto celite and was purified by silicacolumn chromatography to affordrac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas a ˜2:1 mixture of alcohol regioisomers favoring the 5-hydroxyproduct. LC-MS: Rt=1.10 min; MS m/z [M+H]⁺ 379.0.

Example 47a: (Corresponding to Peak 1)(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 47) by Supercritical Fluid Chromatography using the followingconditions afforded the compound listed hereafter:

Method Details:

-   -   Column: 30×250 mm IC @ 30° C.    -   Mobile Phase: 70% CO₂/30% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=3.59 min. LC-MS: Rt=1.10 min; MS m/z [M+H]⁺379.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 8.55-8.52 (m, 2H),7.65-7.62 (m, 2H), 7.44 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.00(dd, J=8.8, 2.4 Hz, 1H), 5.12-4.96 (m, 1H), 4.91-4.86 (m, 1H), 4.26 (s,1H), 4.08-4.04 (m, 1H), 3.53 (d, J=9.7 Hz, 1H), 3.15 (d, J=9.8 Hz, 1H),2.08-2.00 (m, 1H), 1.54-1.47 (m, 1H).

Examples 48-62 described infra were synthesized according to theprotocol described for Example 47 using methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e) and various anilines in Step A and various boronicesters/acids in Step C.

Example 48:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.20 min; MS m/z [M+H]⁺ 393.0. ¹H NMR (500 MHz, DMSO-d₆) δ9.66 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 7.65-7.59 (m, 1H), 7.38 (d, J=8.8Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.11-7.06 (m, 1H), 6.95 (dd, J=8.9, 2.4Hz, 1H), 4.98-4.86 (m, 1H), 4.82 (d, J=5.5, 1.2 Hz, 1H), 4.17 (s, 1H),4.05-4.02 (m, 1H), 3.37-3.32 (m, 1H), 3.00 (d, J=9.7 Hz, 1H), 2.28 (s,3H), 2.04-1.98 (m, 1H), 1.49-1.43 (m, 1H). ˜3:1 mixture of alcoholregioisomers.

Example 49:rac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.32 min; MS m/z [M+H]⁺ 409.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.61 (s, 1H), 7.83 (d, J=5.3 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H), 7.37 (s,1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (dd, J=5.4, 1.5 Hz, 1H), 6.68(s, 1H), 4.96-4.93 (m, 1H), 4.84-4.77 (m, 1H), 4.15 (s, 1H), 4.03-3.98(m, 1H), 3.68 (s, 3H), 3.27 (d, J=9.7 Hz, 1H), 3.01 (d, J=9.8 Hz, 1H),2.03-1.93 (m, 1H), 1.51-1.42 (m, 1H). ˜3:1 mixture of alcoholregioisomers.

Examples 49a and 49b (Corresponding to Peak 1 and Peak 2)(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1S,2R,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 49) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IF @ 30° C.    -   Mobile Phase: 65% CO₂/35% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.10 min. LC-MS: Rt=1.23 min; MS m/z [M+H]⁺409.0. ¹H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.83 (d, J=5.3 Hz, 1H),7.39 (d, J=6.1 Hz, 1H), 7.37 (s, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 6.84(dd, J=5.3, 1.4 Hz, 1H), 6.68 (d, J=0.8 Hz, 1H), 4.97-4.92 (m, 1H),4.86-4.80 (m, 1H), 4.15 (s, 1H), 4.05-3.97 (m, 1H), 3.68 (s, 3H), 3.27(d, J=9.7 Hz, 1H), 3.01 (d, J=9.8 Hz, 1H), 2.02-1.95 (m, 1H), 1.50-1.42(m, 1H).

Peak 2: SFC Retention Time=2.81 min. LC-MS: Rt=1.23 min; MS m/z [M+H]⁺409.0. ¹H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.83 (d, J=5.3 Hz, 1H),7.39 (d, J=6.1 Hz, 1H), 7.37 (s, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 6.84(dd, J=5.3, 1.4 Hz, 1H), 6.68 (d, J=0.8 Hz, 1H), 4.97-4.92 (m, 1H),4.86-4.80 (m, 1H), 4.15 (s, 1H), 4.05-3.97 (m, 1H), 3.68 (s, 3H), 3.27(d, J=9.7 Hz, 1H), 3.01 (d, J=9.8 Hz, 1H), 2.02-1.95 (m, 1H), 1.50-1.42(m, 1H).

Example 50:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.57 min; MS m/z [M+H]⁺ 447.0. Mixture of alcoholregioisomers.

Example 51:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.26 min; MS m/z [M+H]⁺ 380.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.86 (s, 1H), 8.82 (s, 1H), 8.62 (s, 2H), 7.40 (d, J=4.5 Hz, 1H), 7.39(d, J=1.9 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 5.03-4.99 (m, 1H),4.86-4.82 (m, 1H), 4.28 (s, 1H), 4.07-4.02 (m, 1H), 3.38 (d, J=9.7 Hz,1H), 3.05 (d, J=9.7 Hz, 1H), 2.07-2.00 (m, 1H), 1.52-1.44 (m, 1H). ˜3:1mixture of alcohol regioisomers.

Example 52:rac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.39 min; MS m/z [M+H]⁺ 397.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.74 (s, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.40 (d,J=8.8 Hz, 1H), 7.21-7.18 (m, 1H), 7.01 (dd, J=8.8, 2.5 Hz, 1H), 6.96 (s,1H), 5.00-4.97 (m, 1H), 4.87-4.83 (m, 1H), 4.21 (s, 1H), 4.05-4.00 (m,1H), 3.41 (d, J=9.8 Hz, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.05-1.97 (m, 1H),1.52-1.44 (m, 1H). ˜3:1 mixture of alcohol regioisomers.

Examples 52a and 52b (Corresponding to Peak 1 and Peak 2)(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 52) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IF @ 30° C.    -   Mobile Phase: 95-50% CO₂/5-50% MeOH+0.5% isopropylamine in 5        minutes    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=3.15 min. LC-MS: Rt=1.30 min; MS m/z [M+H]⁺397.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 7.95 (d, J=5.2 Hz, 1H),7.44 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.20 (d, J=4.9 Hz, 1H),7.01 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (s, 1H), 5.04-4.95 (m, 1H), 4.89-4.82(m, 1H), 4.21 (s, 1H), 4.05-4.00 (m, 1H), 3.41 (d, J=9.7 Hz, 1H), 3.07(d, J=9.9 Hz, 1H), 2.05-1.96 (m, 1H), 1.52-1.44 (m, 1H).

Peak 2: SFC Retention Time=4.12 min. LC-MS: Rt=1.30 min; MS m/z [M+H]⁺397.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 7.95 (d, J=5.2 Hz, 1H),7.44 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.20 (d, J=4.9 Hz, 1H),7.01 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (s, 1H), 5.04-4.95 (m, 1H), 4.89-4.82(m, 1H), 4.21 (s, 1H), 4.05-4.00 (m, 1H), 3.41 (d, J=9.7 Hz, 1H), 3.07(d, J=9.9 Hz, 1H), 2.05-1.96 (m, 1H), 1.52-1.44 (m, 1H).

Example 53:rac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.18 min; MS m/z [M+H]⁺ 393.0. ˜3:1 mixture of alcoholregioisomers.

Examples 53a and 53b (Corresponding to Peak 1 and Peak 2)(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 53) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 80% CO₂/20% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.14 min. LC-MS: Rt=1.10 min; MS m/z [M+H]⁺393.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (s, 1H), 8.11 (dd, J=5.1, 0.8Hz, 1H), 7.40-7.36 (m, 2H), 7.11 (s, 1H), 7.03-7.00 (m, 1H), 6.98 (dd,J=8.8, 2.4 Hz, 1H), 4.98-4.91 (m, 1H), 4.86-4.80 (m, 1H), 4.17 (s, 1H),4.04-3.99 (m, 1H), 3.25 (d, J=9.7 Hz, 1H), 3.02 (d, J=9.7 Hz, 1H), 2.26(s, 3H), 2.04-1.95 (m, 1H), 1.50-1.42 (m, 1H).

Peak 2: SFC Retention Time=2.79 min. LC-MS: Rt=1.10 min; MS m/z [M+H]⁺393.1. ¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (s, 1H), 8.11 (dd, J=5.1, 0.8Hz, 1H), 7.40-7.36 (m, 2H), 7.11 (s, 1H), 7.03-7.00 (m, 1H), 6.98 (dd,J=8.8, 2.4 Hz, 1H), 4.98-4.91 (m, 1H), 4.86-4.80 (m, 1H), 4.17 (s, 1H),4.04-3.99 (m, 1H), 3.25 (d, J=9.7 Hz, 1H), 3.02 (d, J=9.7 Hz, 1H), 2.26(s, 3H), 2.04-1.95 (m, 1H), 1.50-1.42 (m, 1H).

Example 54:rac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.48 min; MS m/z [M+H]⁺ 447.0. ¹H NMR (500 MHz, DMSO-d₆) δ9.70 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.52 (dd, J=5.1, 1.5Hz, 1H), 7.37-7.33 (m, 2H), 6.96 (dd, J=8.8, 2.4 Hz, 1H), 4.99-4.97 (m,1H), 4.89-4.86 (m, 1H), 4.26 (s, 1H), 4.07-4.03 (m, 1H), 3.49 (d, J=9.7Hz, 1H), 3.10 (d, J=9.9 Hz, 1H), 2.06-2.00 (m, 1H), 1.52-1.46 (m, 1H).˜3:1 mixture of alcohol regioisomers.

Examples 54a and 54b (Corresponding to Peak 1 and Peak 2)(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2R,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 54) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm AD @ 30° C.    -   Mobile Phase: 80% CO₂/20% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=0.80 min. LC-MS: Rt=1.42 min; MS m/z [M+H]⁺447.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.47 (d, J=5.0 Hz, 1H),7.73 (s, 1H), 7.52 (dd, J=5.1, 1.6 Hz, 1H), 7.38-7.34 (m, 2H), 6.96 (dd,J=8.8, 2.4 Hz, 1H), 5.04-4.96 (m, 1H), 4.90-4.84 (m, 1H), 4.25 (s, 1H),4.07-4.00 (m, 1H), 3.49 (d, J=9.8 Hz, 1H), 3.10 (d, J=9.8 Hz, 1H),2.06-1.99 (m, 1H), 1.54-1.45 (m, 1H).

Peak 2: SFC Retention Time=1.28 min. LC-MS: Rt=1.42 min; MS m/z [M+H]⁺447.0. ¹H NMR (400 MHz, DMSO-d₆) δ 9.73 (s, 1H), 8.47 (d, J=5.0 Hz, 1H),7.73 (s, 1H), 7.52 (dd, J=5.1, 1.6 Hz, 1H), 7.38-7.34 (m, 2H), 6.96 (dd,J=8.8, 2.4 Hz, 1H), 5.04-4.96 (m, 1H), 4.90-4.84 (m, 1H), 4.25 (s, 1H),4.07-4.00 (m, 1H), 3.49 (d, J=9.8 Hz, 1H), 3.10 (d, J=9.8 Hz, 1H),2.06-1.99 (m, 1H), 1.54-1.45 (m, 1H).

Example 55:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.28 min; MS m/z [M+H]⁺ 423.0. ¹H NMR (500 MHz, DMSO-d₆) δ9.71 (s, 1H), 8.15 (s, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.4 Hz,1H), 7.03 (dd, J=8.9, 2.4 Hz, 1H), 4.93-4.89 (m, 1H), 4.80-4.77 (m, 1H),4.15 (s, 1H), 4.02-3.97 (m, 1H), 3.16 (d, J=9.5 Hz, 1H), 2.93 (s, 6H),2.91 (d, J=9.5 Hz, 1H), 2.01-1.96 (m, 1H), 1.46-1.40 (m, 1H). ˜3:1mixture of alcohol regioisomers.

Example 56:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.20 min; MS m/z [M+H]⁺ 394.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.81 (s, 1H), 8.49 (s, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.29 (d, J=2.4 Hz,1H), 6.96 (dd, J=8.8, 2.4 Hz, 1H), 4.85-4.79 (m, 1H), 4.59-4.53 (m, 1H),4.24 (s, 1H), 4.06-4.01 (m, 1H), 3.33 (d, J=9.6 Hz, 1H), 3.01 (d, J=9.7Hz, 1H), 2.38 (s, 3H), 2.05-1.98 (m, 1H), 1.50-1.43 (m, 1H). ˜3:1mixture of alcohol regioisomers.

Example 57:(1R,2S,3S,4R,5S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.10 min; MS m/z [M+H]⁺ 394.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.73 (s, 1H), 7.61 (d, J=6.3 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.41 (d,J=8.8 Hz, 1H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 6.86 (s, 2H), 6.64 (s, 1H),6.58-6.55 (m, 1H), 4.98-4.95 (m, 1H), 4.85-4.82 (m, 1H), 4.16 (s, 1H),4.03-3.99 (m, 1H), 3.21 (d, J=9.9 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H),2.01-1.96 (m, 1H), 1.49-1.43 (m, 1H). ˜3:1 mixture of alcoholregioisomers.

Example 58:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2,5-difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.38 min; MS m/z [M+H]⁺ 415.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.98 (s, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.46-7.41 (m, 2H), 7.10-7.05 (m,2H), 5.06-5.01 (m, 1H), 4.85-4.81 (m, 1H), 4.37 (s, 1H), 4.10-4.03 (m,1H), 3.63 (d, J=10.0 Hz, 1H), 3.11 (d, J=9.7 Hz, 1H), 2.06-1.99 (m, 1H),1.52-1.46 (m, 1H). ˜2:1 mixture of alcohol regioisomers.

Example 59:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.40 min; MS m/z [M+H]⁺ 415.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.92 (s, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.45-7.40 (m, 2H), 7.34 (t, J=4.9Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 5.04-5.01 (m, 1H), 4.88-4.83 (m,1H), 4.30 (s, 1H), 4.10-4.05 (m, 1H), 3.70 (d, J=10.0 Hz, 1H), 3.12 (d,J=9.7 Hz, 1H), 2.08-2.00 (m, 1H), 1.53-1.46 (m, 1H). ˜2:1 mixture ofalcohol regioisomers.

Example 60:(1R,2S,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.11 min; MS m/z [M+H]⁺ 395.0. ¹H NMR (500 MHz, DMSO-d₆) δ9.74 (s, 1H), 8.06 (s, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.8 Hz,1H), 7.09-7.06 (m, 1H), 6.25 (s, 2H), 4.92-4.89 (m, 1H), 4.81-4.76 (m,1H), 4.12 (s, 1H), 4.01-3.97 (m, 1H), 3.13 (d, J=9.6 Hz, 1H), 2.91 (d,J=9.8 Hz, 1H), 2.00-1.94 (m, 1H), 1.46-1.40 (m, 1H). ˜3:1 mixture ofalcohol regioisomers.

Example 61:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.33 min; MS m/z [M+H]⁺ 398.0. ¹H NMR (500 MHz, DMSO-d₆) δ9.91 (s, 1H), 8.57 (d, J=1.5 Hz, 2H), 7.42-7.41 (m, 2H), 7.03 (dd,J=8.8, 2.5 Hz, 1H), 5.02-4.98 (m, 1H), 4.86-4.82 (m, 1H), 4.30 (s, 1H),4.06-4.02 (m, 1H), 3.47 (d, J=9.6 Hz, 1H), 3.05 (d, J=9.7 Hz, 1H),2.07-2.01 (m, 1H), 1.52-1.46 (m, 1H). ˜2:1 mixture of alcoholregioisomers.

Example 62:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.03 min; MS m/z [M+H]⁺ 448.1. ¹H NMR (500 MHz, DMSO-d₆) δ9.90 (s, 1H), 8.83 (s, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.4 Hz,1H), 6.94 (dd, J=8.8, 2.5 Hz, 1H), 5.08-5.03 (m, 1H), 4.89-4.85 (m, 1H),4.41 (s, 1H), 4.09-4.05 (m, 1H), 3.53 (d, J=9.6 Hz, 1H), 3.11 (d, J=9.6Hz, 1H), 2.09-2.03 (m, 1H), 1.56-1.47 (m, 1H). ˜3:1 mixture of alcoholregioisomers.

Example 63:(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-methoxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 63 described was synthesized according to the protocol describedfor Example 47 using methyl(1R,4S,5S)-3-bromo-5-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1f) and 3,4-dichloroaniline in Step A and(2-methylpyridin-4-yl)boronic acid in Step C. LC-MS: Rt=1.23 min; MS m/z[M+H]⁺ 407.0. ¹H NMR (500 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.11 (d, J=5.1Hz, 1H), 7.39-7.36 (m, 2H), 7.12 (s, 1H), 7.03 (d, J=5.4 Hz, 1H), 6.99(dd, J=8.9, 2.5 Hz, 1H), 4.86-4.81 (m, 1H), 4.48 (s, 1H), 3.76-3.72 (m,1H), 3.28-3.24 (m, 1H), 3.21 (s, 3H), 3.06 (d, J=9.5 Hz, 1H), 2.27 (s,3H), 2.03-1.97 (m, 1H), 1.54-1.48 (m, 1H). ˜4:1 mixture of methoxyregioisomers.

Example 64:(1R,2S,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(intermediate 4a, Example 48) using Step A as in Scheme 4.

Step A: To a stirring solution of(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(25 mg, 0.064 mmol) in DCM (1 mL) at room temperature was addedXtalfluor-E (36 mg, 0.16 mmol) and Et₃N-3HF (0.031 mL, 0.19 mmol) andthe reaction was stirred for 16 h. The reaction was cooled to 0° C. andwas quenched with saturated aqueous sodium bicarbonate solution. Thecrude compound was extracted with DCM 3×. The combined organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude compound was purified by silica column chromatography to afford(1R,2S,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas an unknown mixture of fluorine regioisomers. LC-MS: Rt=1.38 min; MSm/z [M+H]⁺ 395.0.

Example 65:(1R,2S,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 65 was synthesized according to the protocol described forExample 64 using(1R,2S,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Intermediate 4a, Example 49) in Step A. LC-MS: Rt=1.53 min; MS m/z[M+H]⁺ 411.0. ¹H NMR (500 MHz, DMSO-d₆) δ 10.13 (s, 1H), 7.97-7.94 (m,1H), 7.77 (d, J=2.5 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8,2.5 Hz, 1H), 6.69 (dd, J=5.5, 1.5 Hz, 1H), 6.58 (s, 1H), 5.64 (d, J=72.4Hz, 1H), 4.85-4.80 (m, 1H), 3.79 (s, 3H), 3.70-3.66 (m, 1H), 3.46-3.42(m, 1H), 3.16-3.13 (m, 1H), 1.99-1.95 (m, 1H), 1.79-1.75 (m, 1H). ˜4:1mixture of fluorine regioisomers.

Example 66:(1S,2S,4R,5R,6R,7S)—N-(4-chloro-3-cyanophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Title compound was prepared from methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) using Steps A-B and Step D as in Scheme 2.

Step A: To a stirring solution of methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(1d, 4.70 g, 19.2 mmol) in THF (25 mL) and water (6 mL) at 0° C. wasadded acetic acid (4.40 mL) and portion-wise Zn powder (5.00 g, 77.0mmol). The reaction slurry was stirred to room temperature for 15minutes. The reaction was filtered and neutralized with saturatedaqueous sodium bicarbonate to pH ˜7. The compound was extracted withethyl acetate. The organic layer was washed with water and brine anddried over anhydrous sodium sulfate. The solvent was concentrated anddried under vacuo. The crude compound (1S,2S,4R,5R)-methyl8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate was used in the nextstep without further purification. LC-MS: Rt=1.16 min; MS m/z [M+H]⁺167.1.

Step B: A mixture of (1S,2S,4R,5R)-methyl8-oxatricyclo[3.2.1.02,4]oct-6-ene-6-carboxylate (800 mg, 4.81 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.27g, 5.78 mmol), 2,2-bis(diphenylphosphino)-1,1-binapthalene (300 mg,0.481 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (119 mg, 0.241mol) and potassium carbonate (332 mg, 2.41 mmol) in 1,4-dioxane (10 mL)and water (2.5 mL) was heated at 100° C. for 1 h in the microwave.Celite was added to the reaction mixture and the solvent was removedunder reduced pressure. The compound was purified by FCC to afford(1S,2S,4R,5R,6S,7S)-methyl7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxylate(cis) and (1S,2S,4R,5R,6R,7S)-methyl7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxylate(trans). cis LC-MS: Rt=0.88 min; MS m/z [M+H]⁺ 260.1. trans LC-MS:Rt=0.96 min; MS m/z [M+H]⁺ 260.1.

Step C: To a stirring solution of (1S,2S,4R,5R,6R,7S)-methyl7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxylate(75.0 mg, 0.289 mmol) and 5-amino-2-chlorobenzonitrile (44.0 mg, 0.289mmol) in THF (2 mL) at 0° C. was added LiHMDS (1 M, 0.434 mL, 0.434mmol). The reaction was stirred at room temperature for 1 h. LiHMDS (1M, 0.434 mL, 0.434 mmol) was added and the reaction was continuedstirring at room temperature for 4 h. Celite was added and the solventwas concentrated. The crude compound was purified by FCC to afford thetitle compound(1S,2S,4R,5R,6R,7S)—N-(4-chloro-3-cyanophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide.Method B LC-MS: Rt=1.11 min; MS m/z [M+H]⁺ 380.1. ¹H NMR (400 MHz,DMSO-d₆) δ 10.42 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.22 (d, J=2.5 Hz,1H), 7.77 (dd, J=8.9, 2.5 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.11 (s, 1H),7.05 (d, J=4.0 Hz, 1H), 4.76 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.51 (d,J=4.8 Hz, 1H), 3.09 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.34-1.28 (m, 1H),1.20-1.15 (m, 1H), 0.43-0.39 (m, 1H), 0.21-0.15 (m, 1H).

Examples 67-76 described infra were synthesized according to theprotocol described for Example 66 using methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) and various boronic acids/esters in Step B and variousanilines in Step D.

Example 67:(1S,2S,4R,5R,6R,7S)—N-(4-chloro-2-cyanophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.04 min; MS m/z [M+H]⁺ 380.1. ¹H NMR (400 MHz,DMSO-d₆) δ 10.36 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.04 (d, J=2.5 Hz,1H), 7.77 (dd, J=8.8, 2.5 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.12 (s, 1H),7.06 (dd, J=5.1, 1.3 Hz, 1H), 4.77 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.50(d, J=4.8 Hz, 1H), 3.14 (t, J=4.9 Hz, 1H), 2.43 (s, 3H), 1.42-1.37 (m,1H), 1.33-1.27 (m, 1H), 0.45-0.40 (m, 1H), 0.21-0.17 (m, 1H).

Example 68:(1S,2S,4R,5R,6R,7S)—N-(4-chloro-3-fluorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method C LC-MS: Rt=1.47 min; MS m/z [M+H]⁺ 373.1. ¹H NMR (400 MHz,DMSO-d₆) δ 10.30 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.80 (dd, J=12.0, 2.3Hz, 1H), 7.52 (t, J=8.7 Hz, 1H), 7.31-7.28 (m, 1H), 7.19 (s, 1H), 7.12(d, J=4.9 Hz, 1H), 4.76 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.54 (d, J=4.8Hz, 1H), 3.09 (t, J=4.8 Hz, 1H), 2.45 (s, 3H), 1.33-1.28 (m, 1H),1.18-1.13 (m, 1H), 0.43-0.39 (m, 1H), 0.21-0.15 (m, 1H).

Example 69:(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethoxy)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.47 min; MS m/z [M+H]⁺ 405.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.26 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.46-7.41 (m, 2H),7.12 (s, 1H), 7.08-7.01 (m, 2H), 4.76 (d, J=4.9 Hz, 1H), 4.38 (s, 1H),3.51 (d, J=4.8 Hz, 1H), 3.09 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.35-1.29(m, 1H), 1.19-1.13 (m, 1H), 0.43-0.37 (m, 1H), 0.22-0.16 (m, 1H).

Example 70:(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(5-methylthiazol-2-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.20 min; MS m/z [M+H]⁺ 342.1. ¹H NMR (400 MHz, DMSO-d₆) δ12.12 (s, 1H), 8.55 (d, J=5.9 Hz, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.14(s, 1H), 4.87 (d, J=4.8 Hz, 1H), 4.48 (d, J=1.8 Hz, 1H), 3.73 (d, J=4.6Hz, 1H), 3.21 (d, J=4.9 Hz, 1H), 2.58 (s, 3H), 2.34 (s, 3H), 1.37-1.32(m, 1H), 1.09-1.03 (m, 1H), 0.44-0.38 (m, 1H), 0.23-0.17 (m, 1H).

Example 71:(1S,2S,4R,5R,6R,7S)—N-(3-fluoro-4-(trifluoromethoxy)phenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.50 min; MS m/z [M+H]⁺ 423.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.38 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 7.86 (d, J=12.9 Hz, 1H), 7.52 (t,J=8.9 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 7.25 (s, 1H), 7.19 (d, J=5.4 Hz,1H), 4.78 (d, J=4.5 Hz, 1H), 4.41 (s, 1H), 3.57 (d, J=4.4 Hz, 1H), 3.11(t, J=4.3 Hz, 1H), 2.48 (s, 3H), 1.36-1.28 (m, 1H), 1.21-1.13 (m, 1H),0.44-0.37 (m, 1H), 0.22-0.16 (m, 1H).

Examples 72 and 73 (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamidecarboxamideor(1R,2R,4S,5S,6S,7R)—N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamidecarboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IA @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.61 min. LC-MS: Rt=1.69 min; MS m/z [M+H]⁺412.0. ¹H NMR (500 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.48 (d, J=2.4 Hz,1H), 8.41 (d, J=2.4 Hz, 1H), 8.00 (dd, J=5.2, 1.1 Hz, 1H), 7.37 (t,J=4.9 Hz, 1H), 4.81 (d, J=5.0 Hz, 1H), 4.52 (s, 1H), 3.95 (d, J=4.7 Hz,1H), 3.20-3.11 (m, 1H), 1.38-1.31 (m, 1H), 1.26-1.21 (m, 1H), 0.45-0.39(m, 1H), 0.24-0.16 (m, 1H).

Peak 2: SFC Retention Time=3.23 min. LC-MS: Rt=1.69 min; MS m/z [M+H]⁺412.0. ¹H NMR (500 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.48 (d, J=2.4 Hz,1H), 8.41 (d, J=2.4 Hz, 1H), 8.00 (dd, J=5.2, 1.1 Hz, 1H), 7.37 (t,J=4.9 Hz, 1H), 4.81 (d, J=5.0 Hz, 1H), 4.52 (s, 1H), 3.95 (d, J=4.7 Hz,1H), 3.20-3.11 (m, 1H), 1.38-1.31 (m, 1H), 1.26-1.21 (m, 1H), 0.45-0.39(m, 1H), 0.24-0.16 (m, 1H).

Example 74:(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.28 min; MS m/z [M+H]⁺ 390.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.51 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.32 (d,J=2.1 Hz, 1H), 7.54 (dd, J=8.0, 2.3 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H),4.77 (d, J=4.9 Hz, 1H), 4.32 (s, 1H), 3.54 (d, J=4.7 Hz, 1H), 3.10 (t,J=4.8 Hz, 1H), 2.42 (s, 3H), 1.35-1.29 (m, 1H), 1.24-1.17 (m, 1H),0.44-0.39 (m, 1H), 0.21-0.15 (m, 1H).

Example 75:(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.43 min; MS m/z [M+H]⁺ 377.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.52 (s, 1H), 9.06 (s, 1H), 8.69 (s, 2H), 8.49 (d, J=2.4 Hz, 1H), 8.42(d, J=2.4 Hz, 1H), 4.83 (d, J=4.9 Hz, 1H), 4.43 (s, 1H), 3.62 (d, J=4.7Hz, 1H), 3.22 (t, J=4.8 Hz, 1H), 1.37-1.32 (m, 1H), 1.28-1.21 (m, 1H),0.44-0.40 (m, 1H), 0.22-0.17 (m, 1H).

Example 76:(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.52 min; MS m/z [M+H]⁺ 406.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.52 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.07 (d,J=5.3 Hz, 1H), 6.87 (dd, J=5.3, 1.4 Hz, 1H), 6.65 (s, 1H), 4.76 (d,J=4.9 Hz, 1H), 4.39 (s, 1H), 3.81 (s, 3H), 3.52 (d, J=4.8 Hz, 1H), 3.11(t, J=4.8 Hz, 1H), 1.34-1.27 (m, 1H), 1.23-1.17 (m, 1H), 0.43-0.38 (m,1H), 0.19-0.14 (m, 1H).

Example 77:rac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e) using Steps A-B and Step D as in Scheme 2.

Step A: A solution of methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(le, 1.40 g, 5.62 mmol) and AcOH (1.61 mL, 28.1 mmol) in 1:1 THF:water(15 mL) was treated with Zn powder (735 mg, 11.2 mmol) and was stirredat RT for 1 h. The reaction mixture was diluted with EtOAc and washedwith sat. aq. NaHCO₃ and brine. The aqueous layer was further extractedwith EtOAc and the combined EtOAc layers were dried (Na₂SO₄), filtered,and concentrated. The resulting crude (1R,4R,5S)-methyl5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate and(1S,4S,6R)-methyl 6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylatewas used directly in the next step without purification. LC-MS: Rt=0.29min; MS m/z [M+H]⁺ 171.1.

Step B: A solution of crude (1R,4R,5S)-methyl5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate and(1S,4S,6R)-methyl 6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(250 mg, 1.469 mmol) from Step A,2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (386mg, 1.763 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthalene (91 mg,0.147 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (36.2 mg, 0.073mmol), and potassium carbonate (101 mg, 0.735 mmol) in 4:11,4-dioxane:water (15 mL) was degassed with nitrogen and was warmed at110° C. for 1 h in a microwave reactor. The reaction was repeated on thesame scale a total of four times under identical conditions. Thereaction mixtures were combined and concentrated onto celite andpurified by FCC to afford (1R,2S,3S,4R,5S)-methyl5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylateand (1S,2S,3S,4S,6R)-methyl6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylateas a mixture of alcohol regioisomers (cis) and (1R,2R,3S,4R,5S)-methyl5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylateand (1S,2R,3S,4S,6R)-methyl6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylateas a mixture of alcohol regioisomers (trans). cis: LC-MS: Rt=0.29 min;MS m/z [M+H]⁺ 264.2. trans: LC-MS: Rt=0.33 min; MS m/z [M+H]⁺ 264.2.

Step C: A solution of (1R,2R,3S,4R,5S)-methyl5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylateand (1S,2R,3S,4S,6R)-methyl6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylate(338 mg, 1.284 mmol) and 3,4-dichloroaniline (416 mg, 2.57 mmol) in THF(Volume: 16 mL) at RT was treated with LiHMDS (5.14 mL, 5.14 mmol) andwas stirred at RT for 1 h. The reaction mixture was concentrated ontocelite and was purified by FCC to affordrac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas an ˜8:1 mixture of alcohol regioisomers favoring the 5-hydroxyproduct. LC-MS: Rt=1.20 min; MS m/z [M+H]+ 393.1. ¹H NMR (500 MHz,DMSO-d₆) δ 10.31 (s, 1H), 8.34 (d, J=5.0 Hz, 1H), 7.97 (d, J=2.5 Hz,1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.11 (s, 1H),7.05 (dd, J=5.3, 1.7 Hz, 1H), 4.98-4.95 (m, 1H), 4.90-4.87 (m, 1H), 4.23(s, 1H), 3.98-3.95 (m, 1H), 3.18-3.14 (m, 1H), 2.96-2.93 (m, 1H), 2.43(s, 3H), 2.09-2.04 (m, 1H), 1.45-1.37 (m, 1H).

Examples 77a and 77c (Corresponding to Peak 1 and Peak 3a)(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 77b and 77d (Corresponding to Peak 2 and Peak 3b)(1S,2R,3S,4S,6R)—N-(3,4-dichlorophenyl)-6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1R,2S,3R,4R,6S)—N-(3,4-dichlorophenyl)-6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas an ˜8:1 mixture of alcohol regioisomers (Example 77) by SupercriticalFluid Chromatography using the following conditions afforded thecompounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm AD-H @ 30° C.    -   Mobile Phase: 80% CO₂/20% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.14 min. LC-MS: Rt=1.16 min; MS m/z [M+H]⁺393.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.34 (dd, J=5.2, 0.8Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd,J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H), 7.05 (dd, J=5.2, 1.7 Hz, 1H),5.00-4.97 (m, 1H), 4.91-4.86 (m, 1H), 4.22 (s, 1H), 3.99-3.94 (m, 1H),3.19-3.14 (m, 1H), 2.96-2.92 (m, 1H), 2.43 (s, 3H), 2.10-2.04 (m, 1H),1.44-1.37 (m, 1H).

Peak 2: SFC Retention Time=3.56 min. LC-MS: Rt=1.16 min; MS m/z [M+H]⁺393.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.33 (dd, J=5.2, 0.8Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.44 (dd,J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H), 7.06 (dd, J=5.2, 1.7 Hz, 1H),4.95-4.90 (m, 1H), 4.64-4.59 (m, 1H), 4.57-4.51 (m, 1H), 4.02-3.96 (m,1H), 3.26-3.21 (m, 1H), 3.00-2.95 (m, 1H), 2.42 (s, 3H), 2.10-2.01 (m,1H), 1.55-1.48 (m, 1H).

Peak 3: SFC Retention Time=4.22 min. The third eluted peak isolatedusing Supercritical Fluid Chromatography was concentrated and repurifiedby Supercritical Fluid Chromatography using the following conditions toafford the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm AS-H @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 3a: SFC Retention Time=1.44 min. LC-MS: Rt=1.16 min; MS m/z [M+H]⁺393.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.34 (dd, J=5.2, 0.8Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd,J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H), 7.05 (dd, J=5.2, 1.7 Hz, 1H),5.00-4.97 (m, 1H), 4.91-4.86 (m, 1H), 4.22 (s, 1H), 3.99-3.94 (m, 1H),3.19-3.14 (m, 1H), 2.96-2.92 (m, 1H), 2.43 (s, 3H), 2.10-2.04 (m, 1H),1.44-1.37 (m, 1H).

Peak 3b: SFC Retention Time=2.04 min. LC-MS: Rt=1.16 min; MS m/z [M+H]⁺393.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.33 (dd, J=5.2, 0.8Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.44 (dd,J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H), 7.06 (dd, J=5.2, 1.7 Hz, 1H),4.95-4.90 (m, 1H), 4.64-4.59 (m, 1H), 4.57-4.51 (m, 1H), 4.02-3.96 (m,1H), 3.26-3.21 (m, 1H), 3.00-2.95 (m, 1H), 2.42 (s, 3H), 2.10-2.01 (m,1H), 1.55-1.48 (m, 1H).

Examples 78-91 described infra were synthesized according to theprotocol described for Example 77 using methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e) and various boronic acids/esters in Step B and variousanilines/amines in Step D.

Example 78:(1R,2R,3S,4R,5S)—N-(2-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.89 min; MS m/z [M+H]⁺ 453.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.31 (s, 1H), 8.35 (dd, J=5.2, 0.8 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H),7.51-7.45 (m, 2H), 7.38-7.27 (m, 4H), 7.13 (s, 1H), 7.07 (dd, J=5.2, 1.6Hz, 1H), 5.00-4.97 (m, 1H), 4.94-4.89 (m, 1H), 4.24 (s, 1H), 4.01-3.95(m, 1H), 3.22-3.19 (m, 1H), 3.00-2.96 (m, 1H), 2.44 (s, 3H), 2.12-2.05(m, 1H), 1.46-1.41 (m, 1H). ˜3:1 mixture of alcohol regioisomers.

Example 79:(1R,2R,3S,4R,5S)-5-hydroxy-3-(2-methylpyridin-4-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.20 min; MS m/z [M+H]⁺ 410.2. Mixture of alcoholregioisomers. Example 80:(1R,2R,3S,4R,5S)—N-(4,5-dichloropyridin-2-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.73 min; MS m/z [M+H]⁺ 394.1. ¹H NMR (500 MHz, DMSO-d₆) δ11.03 (s, 1H), 8.52 (s, 1H), 8.37-8.32 (m, 2H), 7.10 (s, 1H), 7.04 (dd,J=5.3, 1.7 Hz, 1H), 5.00-4.95 (m, 1H), 4.95-4.89 (m, 1H), 4.24 (s, 1H),4.00-3.94 (m, 1H), 3.22-3.18 (m, 1H), 3.13-3.09 (m, 1H), 2.43 (s, 3H),2.07-1.99 (m, 1H), 1.43-1.36 (m, 1H). ˜5:1 mixture of alcoholregioisomers.

Example 81:(1R,2R,3S,4R,5S)—N-(5-chloro-6-methylpyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.57 min; MS m/z [M+H]⁺ 374.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.37 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.34 (dd, J=5.2, 0.8 Hz, 1H),8.17 (d, J=2.2 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.06 (dd, J=5.3, 1.7 Hz,1H), 5.00-4.96 (m, 1H), 4.93-4.87 (m, 1H), 4.22 (s, 1H), 3.99-3.91 (m,1H), 3.21-3.15 (m, 1H), 2.99-2.94 (m, 1H), 2.47 (s, 3H), 2.43 (s, 3H),2.11-2.04 (m, 1H), 1.44-1.36 (m, 1H). ˜5:1 mixture of alcoholregioisomers.

Example 82:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.83 min; MS m/z [M+H]⁺ 394.1. Mixture of alcoholregioisomers.

Examples 83 and 84 (Corresponding to Peak 1 and Peak 2A)(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2S,3R,4S,5R)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas a mixture of alcohol regioisomers by Supercritical FluidChromatography using the following conditions afforded the compoundslisted hereafter:

Method Details:

-   -   Column: 21×250 mm IA @ 30° C.    -   Mobile Phase: 80% CO₂/20% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.96 min. LC-MS: Rt=1.05 min; MS m/z [M+H]⁺394.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz,1H), 8.38 (d, J=2.4 Hz, 1H), 8.34 (dd, J=5.2, 0.7 Hz, 1H), 7.12 (s, 1H),7.06 (dd, J=5.2, 1.7 Hz, 1H), 5.02-4.98 (m, 1H), 4.94-4.89 (m, 1H), 4.23(s, 1H), 4.00-3.94 (m, 1H), 3.19-3.15 (m, 1H), 3.01-2.94 (m, 1H), 2.43(s, 3H), 2.12-2.03 (m, 1H), 1.45-1.38 (m, 1H).

Peak 2: The second eluted peak isolated using Supercritical FluidChromatography with Retention Time=3.03 min was concentrated andrepurified by Supercritical Fluid Chromatography using the followingconditions to afford the compound listed hereafter:

Method Details:

-   -   Column: 21×250 mm AD-H @ 30° C.    -   Mobile Phase: 80% CO₂/20% IPA+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 2A: First eluted peak. SFC Retention Time=2.18 min. LC-MS: Rt=1.05min; MS m/z [M+H]⁺ 394.2. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H),8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.34 (dd, J=5.2, 0.7 Hz,1H), 7.12 (s, 1H), 7.06 (dd, J=5.2, 1.7 Hz, 1H), 5.02-4.98 (m, 1H),4.94-4.89 (m, 1H), 4.23 (s, 1H), 4.00-3.94 (m, 1H), 3.19-3.15 (m, 1H),3.01-2.94 (m, 1H), 2.43 (s, 3H), 2.12-2.03 (m, 1H), 1.45-1.38 (m, 1H).

Example 85:(1R,2R,3S,4R,5S)-5-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.13 min; MS m/z [M+H]⁺ 393.3. ¹H NMR (400 MHz, DMSO-d₆) δ10.41 (s, 1H), 8.34 (dd, J=5.2, 0.8 Hz, 1H), 8.09 (s, 1H), 7.73-7.69 (m,1H), 7.57-7.52 (m, 1H), 7.43-7.38 (m, 1H), 7.12 (s, 1H), 7.07 (dd,J=5.2, 1.7 Hz, 1H), 5.02-4.95 (m, 1H), 4.94-4.88 (m, 1H), 4.23 (s, 1H),4.01-3.94 (m, 1H), 3.22-3.17 (m, 1H), 3.00-2.96 (m, 1H), 2.43 (s, 3H),2.13-2.04 (m, 1H), 1.45-1.37 (m, 1H). >20:1 mixture of alcoholregioisomers.

Example 86:(1S,2R,3S,4S,6R)-6-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.12 min; MS m/z [M+H]⁺ 393.3. ¹H NMR (400 MHz, DMSO-d₆) δ10.51 (s, 1H), 8.34 (dd, J=5.2, 0.7 Hz, 1H), 8.12 (s, 1H), 7.76-7.72 (m,1H), 7.59-7.53 (m, 1H), 7.45-7.40 (m, 1H), 7.13-7.10 (m, 1H), 7.07 (dd,J=5.2, 1.7 Hz, 1H), 4.92 (s, 1H), 4.66-4.61 (m, 1H), 4.58-4.53 (m, 1H),4.05-3.98 (m, 1H), 3.28-3.23 (m, 1H), 3.03-2.98 (m, 1H), 2.42 (s, 3H),2.10-2.02 (m, 1H), 1.56-1.46 (m, 1H). >20:1 mixture of alcoholregioisomers.

Example 87:(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.84 min; MS m/z [M+H]⁺ 380.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.60 (s, 1H), 8.50-8.46 (m, 2H), 8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4Hz, 1H), 7.29-7.25 (m, 2H), 5.04-4.99 (m, 1H), 4.96-4.90 (m, 1H), 4.25(s, 1H), 4.02-3.95 (m, 1H), 3.26-3.22 (m, 1H), 3.01-2.96 (m, 1H),2.12-2.04 (m, 1H), 1.48-1.37 (m, 1H). ˜5:1 mixture of alcoholregioisomers.

Example 88:(1R,2R,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.11 min; MS m/z [M+H]⁺ 379.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.47 (s, 1H), 8.49-8.46 (m, 2H), 8.09 (s, 1H), 7.74-7.70 (m, 1H),7.57-7.51 (m, 1H), 7.42-7.37 (m, 1H), 7.29-7.25 (m, 2H), 5.01 (s, 1H),4.96-4.90 (m, 1H), 4.25 (s, 1H), 4.02-3.97 (m, 1H), 3.27-3.22 (m, 1H),3.02-2.98 (m, 1H), 2.14-2.04 (m, 1H), 1.46-1.37 (m, 1H). >20:1 mixtureof alcohol regioisomers.

Example 89:(1S,2R,3S,4S,6R)-6-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.08 min; MS m/z [M+H]⁺ 379.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.56 (s, 1H), 8.50-8.45 (m, 2H), 8.12 (s, 1H), 7.77-7.73 (m, 1H),7.59-7.53 (m, 1H), 7.44-7.40 (m, 1H), 7.29-7.24 (m, 2H), 4.94 (s, 1H),4.69-4.62 (m, 1H), 4.61-4.55 (m, 1H), 4.04-3.97 (m, 1H), 3.32-3.28 (m,1H), 3.06-3.00 (m, 1H), 2.13-2.03 (m, 1H), 1.58-1.48 (m, 1H). >20:1mixture of alcohol regioisomers.

Example 90:rac-(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.30 min; MS m/z [M+H]⁺ 398.1. Mixture of alcoholregioisomers.

Examples 90a and 90b (Corresponding to Peak 1 and Peak 2)(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2S,3R,4S,5R)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 90) as a mixture of alcohol regioisomers by Supercritical FluidChromatography using the following conditions afforded the compoundslisted hereafter:

Method Details:

-   -   Column: 21×250 mm IF @ 30° C.    -   Mobile Phase: 70% CO₂/30% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.29 min. LC-MS: Rt=1.30 min; MS m/z [M+H]⁺398.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz,1H), 8.38 (d, J=2.4 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.27-7.23 (m, 1H),7.02 (s, 1H), 5.06-5.02 (m, 1H), 4.97-4.92 (m, 1H), 4.28 (s, 1H),4.01-3.96 (m, 1H), 3.35-3.33 (m, 1H), 3.04-2.99 (m, 1H), 2.13-2.05 (m,1H), 1.47-1.38 (m, 1H).

Peak 2: SFC Retention Time=1.95 min. LC-MS: Rt=1.30 min; MS m/z [M+H]⁺398.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz,1H), 8.38 (d, J=2.4 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.27-7.23 (m, 1H),7.02 (s, 1H), 5.06-5.02 (m, 1H), 4.97-4.92 (m, 1H), 4.28 (s, 1H),4.01-3.96 (m, 1H), 3.35-3.33 (m, 1H), 3.04-2.99 (m, 1H), 2.13-2.05 (m,1H), 1.47-1.38 (m, 1H).

Example 91:(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.35 min; MS m/z [M+H]⁺ 416.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.61 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.01 (dd,J=5.2, 1.2 Hz, 1H), 7.42-7.37 (m, 1H), 5.11-5.08 (m, 1H), 4.96-4.93 (m,1H), 4.36 (s, 1H), 4.02-3.97 (m, 1H), 3.64-3.60 (m, 1H), 3.05-3.02 (m,1H), 2.15-2.07 (m, 1H), 1.49-1.40 (m, 1H). ˜5:1 mixture of alcoholregioisomers.

Examples 92-102 described infra were synthesized according to theprotocol described for Example 77 using methyl(1R,4S,5R)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6S)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1g) and various boronic acids/esters in Step B and variousanilines in Step D.

Examples 92 and 94 (Corresponding to Peak 1 and Peak 3)(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1S,2S,3R,4S,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Examples 93 and 95 (Corresponding to Peak 2 and Peak 4)(1S,2R,3S,4S,6S)—N-(3,4-dichlorophenyl)-6-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1R,2S,3R,4R,6R)—N-(3,4-dichlorophenyl)-6-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas a mixture of fluorine regioisomers by Supercritical FluidChromatography using the following conditions afforded the compoundslisted hereafter:

Method Details:

-   -   Column: 21×250 mm IF @ 30° C.    -   Mobile Phase: 95-50% CO₂/5-50% MeOH+0.5% isopropylamine in 5        minutes    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.45 min. LC-MS: Rt=1.35 min; MS m/z [M+H]⁺395.1. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.50 (s, 1H), 8.36 (dd,J=5.2, 0.8 Hz, 1H), 7.88 (dd, J=2.3, 0.6 Hz, 1H), 7.46-7.39 (m, 2H),7.16 (s, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 5.24-5.02 (m, 1H), 4.92-4.87(m, 1H), 4.65-4.58 (m, 1H), 4.09-4.02 (m, 1H), 3.18-3.11 (m, 1H), 2.46(s, 3H), 2.23-2.16 (m, 1H), 1.91-1.79 (m, 1H).

Peak 2: SFC Retention Time=2.75 min. LC-MS: Rt=1.35 min; MS m/z [M+H]⁺395.1. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.61 (s, 1H), 8.36 (dd,J=5.2, 0.7 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H),7.40-7.37 (m, 1H), 7.13 (s, 1H), 7.07 (dd, J=5.2, 1.7 Hz, 1H), 5.12-4.97(m, 1H), 4.97-4.95 (m, 1H), 4.68-4.62 (m, 1H), 3.26-3.20 (m, 1H),2.97-2.91 (m, 1H), 2.46 (s, 3H), 2.41-2.29 (m, 1H), 1.83-1.68 (m, 1H).

Peak 3: SFC Retention Time=2.85 min. LC-MS: Rt=1.35 min; MS m/z [M+H]⁺395.1. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.50 (s, 1H), 8.36 (dd,J=5.2, 0.8 Hz, 1H), 7.88 (dd, J=2.3, 0.6 Hz, 1H), 7.46-7.39 (m, 2H),7.16 (s, OH), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 5.24-5.02 (m, 1H), 4.92-4.87(m, 1H), 4.65-4.58 (m, 1H), 4.09-4.02 (m, 1H), 3.18-3.11 (m, 1H), 2.46(s, 3H), 2.23-2.16 (m, 1H), 1.91-1.79 (m, 1H).

Peak 4: SFC Retention Time=3.12 min. LC-MS: Rt=1.35 min; MS m/z [M+H]⁺395.1. ¹H NMR (400 MHz, Acetonitrile-d₃) δ 8.61 (s, 1H), 8.36 (dd,J=5.2, 0.7 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H),7.40-7.37 (m, 1H), 7.13 (s, 1H), 7.07 (dd, J=5.2, 1.7 Hz, 1H), 5.12-4.97(m, 1H), 4.97-4.95 (m, 1H), 4.68-4.62 (m, 1H), 3.26-3.20 (m, 1H),2.97-2.91 (m, 1H), 2.46 (s, 3H), 2.41-2.29 (m, 1H), 1.83-1.68 (m, 1H).

Example 96:(1R,2R,3S,4R,5R)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.29 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.38 (s, 1H), 8.37 (dd, J=5.1, 0.8 Hz, 1H), 8.10 (s, 1H), 7.75-7.71 (m,1H), 7.55 (t, J=8.0 Hz, 1H), 7.45-7.39 (m, 1H), 7.16 (s, 1H), 7.10 (dd,J=5.2, 1.7 Hz, 1H), 5.25-5.03 (m, 1H), 5.01-4.95 (m, 1H), 4.74-4.68 (m,1H), 4.06-3.98 (m, 1H), 3.25-3.20 (m, 1H), 2.44 (s, 3H), 2.25-2.10 (m,1H), 1.82-1.70 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 97:(1R,2R,3S,4R,5R)-5-fluoro-N-(6-methoxypyridin-3-yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.92 min; MS m/z [M+H]⁺ 358.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.06 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.31 (dd, J=2.7, 0.7 Hz, 1H),7.87 (dd, J=8.9, 2.7 Hz, 1H), 7.15 (s, 1H), 7.09 (dd, J=5.2, 1.7 Hz,1H), 6.79 (dd, J=8.8, 0.7 Hz, 1H), 5.24-5.04 (m, 1H), 4.97-4.91 (m, 1H),4.71-4.66 (m, 1H), 4.02-3.98 (m, 1H), 3.80 (s, 3H), 3.22-3.15 (m, 1H),2.44 (s, 3H), 2.24-2.09 (m, 1H), 1.82-1.70 (m, 1H). >20:1 mixture offluorine regioisomers.

Example 98:(1R,2R,3S,4R,5R)—N-(5,6-dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.21 min; MS m/z [M+H]⁺ 396.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.59 (s, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.37 (d,J=5.1 Hz, 1H), 7.17-7.14 (m, 1H), 7.09 (dd, J=5.2, 1.7 Hz, 1H),5.26-5.05 (m, 1H), 5.01-4.94 (m, 1H), 4.75-4.67 (m, 1H), 4.03-3.97 (m,1H), 3.27-3.21 (m, 1H), 2.44 (s, 3H), 2.24-2.11 (m, 1H), 1.81-1.67 (m,1H). >20:1 mixture of fluorine regioisomers.

Example 99:(1R,2R,3S,4R,5R)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethoxy)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.30 min; MS m/z [M+H]⁺ 411.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.34 (s, 1H), 8.38 (dd, J=5.2, 0.8 Hz, 1H), 7.78 (s, 1H), 7.49-7.41 (m,2H), 7.19-7.15 (m, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 7.08-7.04 (m, 1H),5.26-5.04 (m, 1H), 4.99-4.94 (m, 1H), 4.75-4.66 (m, 1H), 4.04-4.00 (m,1H), 3.25-3.20 (m, 1H), 2.45 (s, 3H), 2.24-2.09 (m, 1H), 1.81-1.68 (m,1H). >20:1 mixture of fluorine regioisomers.

Example 100:(1R,2R,3S,4R,5R)-5-fluoro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.36 min; MS m/z [M+H]⁺ 429.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.43 (s, 1H), 8.37 (d, J=0.7 Hz, 1H), 7.84 (dd, J=12.9, 2.5 Hz, 1H),7.55-7.50 (m, 1H), 7.36-7.32 (m, 1H), 7.15 (s, 1H), 7.09 (dd, J=5.2, 1.7Hz, 1H), 5.25-5.04 (m, 1H), 4.99-4.93 (m, 1H), 4.74-4.68 (m, 1H),4.03-3.99 (m, 1H), 3.25-3.17 (m, 1H), 2.44 (s, 3H), 2.23-2.10 (m, 1H),1.79-1.65 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 101:(1R,2R,3S,4R,5R)-5-fluoro-N-(1-methyl-1H-pyrazol-3-yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.43 min; MS m/z [M+H]⁺ 331.3. ¹H NMR (400 MHz, DMSO-d₆) δ10.54 (s, 1H), 8.36 (dd, J=5.1, 0.8 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H),7.12 (s, 1H), 7.06 (dd, J=5.2, 1.7 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H),5.22-5.01 (m, 1H), 4.95-4.89 (m, 1H), 4.70-4.65 (m, 1H), 4.03-3.98 (m,1H), 3.71 (s, 3H), 3.20-3.15 (m, 1H), 2.44 (s, 3H), 2.19-2.06 (m, 1H),1.75-1.61 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 102:(1R,2R,3S,4R,5R)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(5-methylthiazol-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.04 min; MS m/z [M+H]⁺ 348.2. ¹H NMR (400 MHz, DMSO-d₆) δ12.11 (s, 1H), 8.37 (dd, J=5.1, 0.7 Hz, 1H), 7.16-7.11 (m, 2H), 7.08(dd, J=5.3, 1.7 Hz, 1H), 5.25-5.04 (m, 1H), 5.02-4.97 (m, 1H), 4.75-4.69(m, 1H), 4.06-4.00 (m, 1H), 3.33-3.27 (m, 1H), 2.44 (s, 3H), 2.34 (s,3H), 2.24-2.10 (m, 1H), 1.68-1.53 (m, 1H). ˜8:1 mixture of fluorineregioisomers.

Examples 103-116 described infra were synthesized according to theprotocol described for Example 77 using methyl(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1j) and various boronic acids/esters in Step B and variousanilines in Step D.

Example 103:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.54 min; MS m/z [M+H]⁺ 411.2. ¹H NMR (500 MHz, DMSO-d₆) δ10.37 (s, 1H), 8.10 (dd, J=5.3, 0.7 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H),7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.4 Hz, 1H), 6.88 (dd, J=5.4,1.5 Hz, 1H), 6.66 (s, 1H), 5.16-5.01 (m, 1H), 5.01-4.98 (m, 1H), 4.67(d, J=10.6 Hz, 1H), 3.83 (s, 3H), 3.24-3.19 (m, 1H), 3.02-2.96 (m, 1H),2.30-2.20 (m, 1H), 1.79-1.64 (m, 1H). >20:1 mixture of fluorineregioisomers.

Example 104:(1S,2R,3S,4S,6R)—N-(3,4-dichlorophenyl)-6-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.55 min; MS m/z [M+H]⁺ 411.1. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.55 (s, 1H), 8.07 (dd, J=5.4, 0.7 Hz, 1H), 7.86 (d,J=2.4 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.8, 2.4 Hz, 1H),6.87 (dd, J=5.3, 1.5 Hz, 1H), 6.67 (dd, J=1.5, 0.7 Hz, 1H), 5.11-4.92(m, 2H), 4.67-4.59 (m, 1H), 3.86 (s, 3H), 3.27-3.21 (m, 1H), 2.97-2.90(m, 1H), 2.43-2.31 (m, 1H), 1.84-1.65 (m, 1H). >20:1 mixture of fluorineregioisomers.

Example 105:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.31 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.56 (s, 1H), 8.36 (dd, J=5.2, 0.8 Hz, 1H), 7.87 (d,J=2.4 Hz, 1H), 7.45-7.38 (m, 2H), 7.13 (s, 1H), 7.08-7.06 (m, 1H),5.13-4.93 (m, 2H), 4.68-4.63 (m, 1H), 3.26-3.22 (m, 1H), 2.96-2.91 (m,1H), 2.46 (s, 3H), 2.40-2.30 (m, 1H), 1.85-1.77 (m, 1H). >20:1 mixtureof fluorine regioisomers.

Example 106:(1S,2R,3S,4S,6R)—N-(3,4-dichlorophenyl)-6-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.31 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.52 (s, 1H), 8.36 (dd, J=5.2, 0.8 Hz, 1H), 7.89 (d,J=2.0 Hz, 1H), 7.45-7.38 (m, 2H), 7.18-7.15 (m, 1H), 7.10 (dd, J=5.2,1.7 Hz, 1H), 5.23-5.03 (m, 1H), 4.91-4.86 (m, 1H), 4.64-4.59 (m, 1H),4.08-4.05 (m, 1H), 3.19-3.13 (m, 1H), 2.46 (s, 3H), 2.20-2.11 (m, 1H),1.91-1.79 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 107:(1R,2R,3S,4R,5S)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.29 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.72 (s, 1H), 8.35 (dd, J=5.2, 0.8 Hz, 1H), 8.02 (s,1H), 7.68-7.62 (m, 1H), 7.52-7.46 (m, 1H), 7.42-7.36 (m, 1H), 7.14 (s,1H), 7.07 (dd, J=5.2, 1.7 Hz, 1H), 5.13-4.95 (m, 2H), 4.70-4.63 (m, 1H),3.29-3.23 (m, 1H), 2.99-2.92 (m, 1H), 2.45 (s, 3H), 2.43-2.34 (m, 1H),1.86-1.67 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 108:(1S,2R,3S,4S,6R)-6-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.29 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.59 (s, 1H), 8.37 (dd, J=5.2, 0.8 Hz, 1H), 8.03 (s,1H), 7.71-7.67 (m, 1H), 7.53-7.47 (m, 1H), 7.42-7.37 (m, 1H), 7.18 (s,1H), 7.11 (dd, J=5.3, 1.7 Hz, 1H), 5.24-5.03 (m, 1H), 4.94-4.89 (m, 1H),4.66-4.60 (m, 1H), 4.12-4.07 (m, 1H), 3.21-3.16 (m, 1H), 2.46 (s, 3H),2.24-2.14 (m, 1H), 1.90-1.81 (m, 1H). >20:1 mixture of fluorineregioisomers.

Example 109:(1R,2R,3S,4R,5S)—N-(5,6-dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.22 min; MS m/z [M+H]⁺ 396.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.73 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.36 (dd,J=5.2, 0.8 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.14-7.13 (m, 1H), 7.07 (dd,J=5.3, 1.7 Hz, 1H), 5.13-4.94 (m, 2H), 4.69-4.62 (m, 1H), 3.27-3.21 (m,1H), 3.00-2.94 (m, 1H), 2.46 (s, 3H), 2.40-2.30 (m, 1H), 1.86-1.67 (m,1H). >20:1 mixture of fluorine regioisomers.

Example 110:(1S,2R,3S,4S,6R)—N-(5,6-dichloropyridin-3-yl)-6-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.22 min; MS m/z [M+H]⁺ 396.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.69 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.37 (dd,J=5.2, 0.8 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.17 (s, 1H), 7.10 (dd,J=5.2, 1.7 Hz, 1H), 5.24-5.04 (m, 1H), 4.93-4.89 (m, 1H), 4.64-4.60 (m,1H), 4.09-4.05 (m, 1H), 3.22-3.18 (m, 1H), 2.46 (s, 3H), 2.25-2.14 (m,1H), 1.90-1.78 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 111:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.59 min; MS m/z [M+H]⁺ 399.1. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.55 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.86 (d, J=2.4Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 7.23-7.20(m, 1H), 6.97-6.93 (m, 1H), 5.13-4.95 (m, 2H), 4.70-4.65 (m, 1H),3.39-3.34 (m, 1H), 2.99-2.94 (m, 1H), 2.41-2.30 (m, 1H), 1.85-1.69 (m,1H). >20:1 mixture of fluorine regioisomers.

Example 112:(1S,2R,3S,4S,6R)—N-(3,4-dichlorophenyl)-6-fluoro-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.59 min; MS m/z [M+H]⁺ 399.1. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.50 (s, 1H), 8.13 (dd, J=5.2, 0.7 Hz, 1H), 7.88 (d,J=2.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.27-7.23 (m, 1H), 6.99-6.97 (m, 1H),5.25-5.04 (m, 1H), 4.94-4.89 (m, 1H), 4.68-4.65 (m, 1H), 4.21-4.17 (m,1H), 3.20-3.15 (m, 1H), 2.25-2.17 (m, 1H), 1.91-1.80 (m, 1H). ˜5:1mixture of fluorine regioisomers.

Example 113:(1R,2R,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-fluoro-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.33 min; MS m/z [M+H]⁺ 397.2. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.57 (s, 1H), 8.18 (s, 2H), 7.85 (d, J=2.4 Hz, 1H),7.43 (d, J=8.8 Hz, 1H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 5.37 (s, 2H),5.10-4.92 (m, 2H), 4.56-4.51 (m, 1H), 3.11-3.07 (m, 1H), 2.93-2.89 (m,1H), 2.44-2.33 (m, 1H), 1.81-1.65 (m, 1H). >20:1 mixture of fluorineregioisomers.

Example 114:(1S,2R,3S,4S,6R)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-6-fluoro-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.33 min; MS m/z [M+H]⁺ 397.2. ¹H NMR (400 MHz,Acetonitrile-d₃) δ 8.50 (s, 1H), 8.22 (s, 2H), 7.87 (dd, J=2.2, 0.6 Hz,1H), 7.44-7.39 (m, 2H), 5.36 (s, 2H), 5.20-5.01 (m, 1H), 4.89-4.84 (m,1H), 4.54-4.50 (m, 1H), 3.94-3.90 (m, 1H), 3.14-3.07 (m, 1H), 2.21-2.10(m, 1H), 1.93-1.83 (m, 1H). ˜5:1 mixture of fluorine regioisomers.

Example 115:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.32 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.55 (s, 1H), 8.37-8.34 (m, 1H), 7.86 (d, J=2.4 Hz,1H), 7.57 (dd, J=8.1, 2.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.37 (dd,J=8.8, 2.4 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 5.14-4.93 (m, 2H), 4.61-4.55(m, 1H), 3.27-3.23 (m, 1H), 2.97-2.92 (m, 1H), 2.45 (s, 3H), 2.44-2.33(m, 1H), 1.83-1.67 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 116:(1S,2R,3S,4S,6R)—N-(3,4-dichlorophenyl)-6-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.32 min; MS m/z [M+H]⁺ 395.2. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.57 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.86 (d, J=2.1Hz, 1H), 7.60 (dd, J=8.1, 2.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.16 (d, J=8.0Hz, 1H), 5.21-5.01 (m, 1H), 4.91-4.86 (m, 1H), 4.58-4.54 (m, 1H),4.12-4.06 (m, 1H), 3.18-3.11 (m, 1H), 2.45 (s, 3H), 2.21-2.10 (m, 1H),1.92-1.81 (m, 1H). >20:1 mixture of fluorine regioisomers.

Example 117:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Title compound was prepared from methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) using Steps A-C as in Scheme 3.

Step A: To a stirring solution of 3,4-dichloroaniline (568 mg, 3.51mmol) in anhydrous toluene (10 mL) at 0° C. under N₂ was addedtrimethylaluminum in toluene (2 M, 3.9 mL, 7.79 mmol). After 10 minutes,the ice bath was removed and the mixture was stirred at room temperaturefor 30 minutes. The reaction was cooled back to 0° C. and 1d (955 mg,3.90 mmol, dissolved in 2 mL of toluene) was added and the reaction wasstirred at room temperature for 6 h. The reaction was cooled to 0° C.and quenched with a solution of saturated aqueous NH₄Cl and methanol.The suspension was filtered and the solid was washed with EtOAc. Theorganic layer was separated and washed with brine and dried overanhydrous sodium sulfate and concentrated. The crude compound waspurified by silica column chromatography using DCM and EtOAc to afford(1S,2S,4R,5R)-7-bromo-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide.LC-MS: Rt=1.63 min; MS m/z [M+H]⁺ 373.9. ¹H NMR (400 MHz, DMSO-d₆) δ10.10 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.65 (dd, J=8.9, 2.3 Hz, 1H),7.60 (d, J=8.8 Hz, 1H), 5.15 (s, 1H), 4.87 (s, 1H), 1.70-1.66 (m, 1H),1.60-1.55 (m, 1H), 1.42-1.39 (m, 1H), 1.02-0.98 (m, 1H).

Step B: To a stirring solution of(1S,2S,4R,5R)-7-bromo-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide(525 mg, 1.40 mmol) in THF (10 mL) and water (2.5 mL) at 0° C. was addedacetic acid (0.321 mL) and portion-wise Zn powder (366 mg, 5.60 mmol).The reaction slurry was stirred to room temperature for 15 minutes. Thereaction was filtered and neutralized with saturated sodium bicarbonateto pH ˜7. The compound was extracted with ethyl acetate. The organiclayer was washed with water and brine and dried over anhydrous sodiumsulfate and concentrated. The crude compound was purified by silicacolumn chromatography (hexanes:EtOAc) to afford(1S,2S,4R,5R)—N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide.LC-MS: Rt=1.54 min; MS m/z [M+H]⁺ 296.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.11 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.9, 2.4 Hz, 1H),7.59 (d, J=8.8 Hz, 1H), 7.37 (d, J=1.7 Hz, 1H), 4.98 (s, 1H), 4.89 (d,J=1.7 Hz, 1H), 1.42-1.36 (m, 3H), 0.96-0.90 (m, 1H).

Step C: A mixture of(1S,2S,4R,5R)—N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxamide(150 mg, 0.507 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (133mg, 0.608 mmol), 2,2-bis(diphenylphosphino)-1,1-binapthalene (32 mg,0.051 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (12 mg, 0.025mmol) and potassium carbonate (35.0 mg, 0.253 mmol) in 1,4-dioxane (2mL) and water (0.5 mL) was heated in the microwave at 100° C. for 1 h.The crude reaction was taken in celite and the solvent was concentratedto dryness. The crude compound was purified by silica columnchromatography to afford(1S,2S,4R,5R,6S,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(cis) and(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 117). Method B LC-MS: Rt=1.33 min; MS m/z [M+H]⁺ 389.0. ¹H NMR(400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.02 (d,J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H),7.12-7.10 (m, 1H), 7.05 (dd, J=5.2, 1.6 Hz, 1H), 4.75 (d, J=4.9 Hz, 1H),4.38 (s, 1H), 3.50 (d, J=4.8 Hz, 1H), 3.07 (t, J=4.8 Hz, 1H), 2.42 (s,3H), 1.33-1.28 (m, 1H), 1.18-1.13 (m, 1H), 0.43-0.39 (m, 1H), 0.21-0.15(m, 1H).

Examples 118-137 described infra were synthesized according to theprotocol described for Example 117 using methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0^(2,4)]oct-6-ene-6-carboxylate(Intermediate 1d) and various anilines in Step A and various boronicesters/acids in Step C.

Example 118:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.59 min; MS m/z [M+H]⁺ 405.1. ¹H NMR (400 MHz,DMSO-d₆) δ 10.27 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 8.01 (d, J=2.4 Hz,1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 6.87 (dd,J=5.3, 1.4 Hz, 1H), 6.47-6.45 (m, 1H), 4.75 (d, J=4.9 Hz, 1H), 4.38 (s,1H), 3.81 (s, 3H), 3.51 (d, J=4.8 Hz, 1H), 3.07 (t, J=4.9 Hz, 1H),1.33-1.28 (m, 1H), 1.19-1.13 (m, 1H), 0.42-0.39 (m, 1H), 0.20-0.15 (m,1H).

Example 119:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-fluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.71 min; MS m/z [M+H]⁺ 393.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.27 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.02 (d, J=2.4 Hz,1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.23 (dt,J=5.2, 1.8 Hz, 1H), 7.00 (s, 1H), 4.79 (d, J=4.9 Hz, 1H), 4.44 (s, 1H),3.65 (d, J=4.8 Hz, 1H), 3.12 (t, J=4.8 Hz, 1H), 1.34-1.30 (m, 1H),1.20-1.16 (m, 1H), 0.43-0.40 (m, 1H), 0.19-0.17 (m, 1H).

Example 120:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridin-2-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.84 min; MS m/z [M+H]⁺ 443.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.38 (s, 1H), 8.06 (t, J=7.8 Hz, 1H), 8.02 (d, J=2.4 Hz,1H), 7.76 (d, J=7.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.8 Hz,1H), 7.48 (dd, J=8.8, 2.4 Hz, 1H), 4.77 (d, J=5.0 Hz, 1H), 4.50 (s, 1H),3.87 (d, J=4.8 Hz, 1H), 3.68 (t, J=4.9 Hz, 1H), 1.41-1.37 (m, 1H),1.19-1.14 (m, 1H), 0.42-0.40 (m, 1H), 0.21-0.16 (m, 1H).

Example 121:rac-(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.30 min; MS m/z [M+H]⁺ 389.1. ¹H NMR (400 MHz,DMSO-d₆) δ 10.34 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.74 (d,J=8.4 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.12 (s,1H), 7.06 (d, J=5.1 Hz, 1H), 4.77 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.52(d, J=4.8 Hz, 1H), 3.10 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.33-1.28 (m,1H), 1.21-1.16 (m, 1H), 0.43-0.38 (m, 1H), 0.21-0.15 (m, 1H).

Examples 121a and 121b (corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxamideor(1R,2R,4S,5S,6S,7R)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 121) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IB @ 30° C.    -   Mobile Phase: 90% CO₂/10% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.28 min. LC-MS: Rt=1.43 min; MS m/z [M+H]⁺389.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.34 (d, J=5.1 Hz,1H), 8.13 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.41(d, J=7.7 Hz, 1H), 7.12 (s, 1H), 7.06 (dd, J=5.1, 1.4 Hz, 1H), 4.77 (d,J=4.9 Hz, 1H), 4.39 (s, 1H), 3.52 (d, J=4.8 Hz, 1H), 3.10 (t, J=4.8 Hz,1H), 2.42 (s, 3H), 1.34-1.28 (m, 1H), 1.21-1.15 (m, 1H), 0.43-0.38 (m,1H), 0.22-0.15 (m, 1H).

Peak 2: SFC Retention Time=1.66 min. LC-MS: Rt=1.43 min; MS m/z [M+H]⁺389.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.34 (d, J=5.1 Hz,1H), 8.13 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.41(d, J=7.7 Hz, 1H), 7.12 (s, 1H), 7.06 (dd, J=5.1, 1.4 Hz, 1H), 4.77 (d,J=4.9 Hz, 1H), 4.39 (s, 1H), 3.52 (d, J=4.8 Hz, 1H), 3.10 (t, J=4.8 Hz,1H), 2.42 (s, 3H), 1.34-1.28 (m, 1H), 1.21-1.15 (m, 1H), 0.43-0.38 (m,1H), 0.22-0.15 (m, 1H).

Example 122:rac-(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.73 min; MS m/z [M+H]⁺ 411.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.29 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.00 (d, J=5.2 Hz,1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (t,J=4.9 Hz, 1H), 4.79 (d, J=4.9 Hz, 1H), 4.51 (s, 1H), 3.94 (d, J=4.7 Hz,1H), 3.12 (t, J=4.8 Hz, 1H), 1.36-1.31 (m, 1H), 1.21-1.16 (m, 1H),0.44-0.40 (m, 1H), 0.22-0.17 (m, 1H).

Examples 122a and 122b (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6S,7R)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 122) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IB @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.86 min. Method D LC-MS: Rt=1.79 min; MS m/z[M+H]+ 411.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.03-7.97 (m,2H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (t,J=4.9 Hz, 1H), 4.79 (d, J=4.9 Hz, 1H), 4.51 (s, 1H), 3.94 (d, J=4.7 Hz,1H), 3.12 (t, J=4.8 Hz, 1H), 1.37-1.31 (m, 1H), 1.22-1.17 (m, 1H),0.45-0.39 (m, 1H), 0.22-0.17 (m, 1H).

Peak 2: SFC Retention Time=2.43 min. LC-MS: Rt=1.79 min; MS m/z [M+H]⁺410.8. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.03-7.97 (m, 2H),7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (t, J=4.9 Hz,1H), 4.79 (d, J=4.9 Hz, 1H), 4.51 (s, 1H), 3.94 (d, J=4.7 Hz, 1H), 3.12(t, J=4.8 Hz, 1H), 1.37-1.31 (m, 1H), 1.22-1.17 (m, 1H), 0.45-0.39 (m,1H), 0.22-0.17 (m, 1H).

Example 123:(1S,2S,4R,5R,6R,7S)—N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.03 min; MS m/z [M+H]⁺ 352.0. ¹H NMR (400 MHz, DMSO-d₆) δ9.97 (s, 1H), 8.34-8.32 (m, 1H), 8.31 (d, J=2.1 Hz, 1H), 7.87 (dd,J=8.9, 2.7 Hz, 1H), 7.53 (dd, J=8.0, 2.4 Hz, 1H), 7.19 (d, J=8.0 Hz,1H), 6.79 (dd, J=8.9, 0.5 Hz, 1H), 4.74 (d, J=4.9 Hz, 1H), 4.29 (s, 1H),3.80 (s, 3H), 3.53 (d, J=4.8 Hz, 1H), 3.05 (t, J=4.8 Hz, 1H), 2.42 (s,3H), 1.33-1.27 (m, 1H), 1.22-1.16 (m, 1H), 0.44-0.39 (m, 1H), 0.21-0.15(m, 1H).

Example 124:(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method C LC-MS: Rt=1.49 min; MS m/z [M+H]⁺ 411.8. ¹H NMR (400 MHz,DMSO-d₆) δ 10.59 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz,1H), 8.00 (d, J=5.1 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 4.81 (d, J=4.9 Hz,1H), 4.52 (s, 1H), 3.94 (d, J=4.7 Hz, 1H), 3.17 (t, J=4.8 Hz, 1H),1.36-1.30 (m, 1H), 1.26-1.20 (m, 1H), 0.45-0.39 (m, 1H), 0.23-0.18 (m,1H).

Example 125:(1S,2S,4R,5R,6R,7S)—N-(6-methoxypyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.01 min; MS m/z [M+H]⁺ 338.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.00 (s, 1H), 8.48 (d, J=5.3 Hz, 2H), 8.35-8.32 (m, 1H), 7.87 (dd,J=8.9, 2.7 Hz, 1H), 7.28-7.24 (m, 2H), 6.82-6.77 (m, 1H), 4.76 (d, J=4.9Hz, 1H), 4.39 (s, 1H), 3.81 (s, 3H), 3.56 (d, J=4.8 Hz, 1H), 3.08 (t,J=4.8 Hz, 1H), 1.34-1.28 (m, 1H), 1.21-1.16 (m, 1H), 0.44-0.39 (m, 1H),0.21-0.15 (m, 1H).

Example 126:rac-(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.46 min; MS m/z [M+H]⁺ 376.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.26 (s, 1H), 9.06 (s, 1H), 8.68 (s, 2H), 8.02 (d, J=2.4 Hz,1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (d,J=4.9 Hz, 1H), 4.42 (s, 1H), 3.61 (d, J=4.7 Hz, 1H), 3.17 (t, J=4.8 Hz,1H), 1.36-1.30 (m, 1H), 1.21-1.16 (m, 1H), 0.45-0.39 (m, 1H), 0.22-0.17(m, 1H).

Examples 126a and 126b (Corresponding to Peak 1 and Peak 2)(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamideor(1R,2R,4S,5S,6S,7R)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Chiral separation ofrac-(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide(Example 126) by Supercritical Fluid Chromatography using the followingconditions afforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IB @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.88 min. Method B LC-MS: Rt=1.44 min; MS m/z[M+H]+ 375.8. ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 9.06 (s, 1H),8.68 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd,J=8.8, 2.4 Hz, 1H), 4.82 (d, J=4.9 Hz, 1H), 4.42 (s, 1H), 3.61 (d, J=4.7Hz, 1H), 3.18 (t, J=4.8 Hz, 1H), 1.36-1.29 (m, 1H), 1.22-1.17 (m, 1H),0.44-0.39 (m, 1H), 0.23-0.17 (m, 1H).

Peak 2: SFC Retention Time=2.43 min. Method B LC-MS: Rt=1.44 min; MS m/z[M+H]+ 375.9. ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 9.06 (s, 1H),8.68 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd,J=8.8, 2.4 Hz, 1H), 4.82 (d, J=4.9 Hz, 1H), 4.42 (s, 1H), 3.61 (d, J=4.7Hz, 1H), 3.18 (t, J=4.8 Hz, 1H), 1.36-1.29 (m, 1H), 1.22-1.17 (m, 1H),0.44-0.39 (m, 1H), 0.23-0.17 (m, 1H).

Example 127:(1S,2S,4R,5R,6R,7S)-7-(2,3-difluoropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.44 min; MS m/z [M+H]⁺ 374.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.02 (s, 1H), 8.35-8.32 (m, 1H), 8.00 (dd, J=5.0, 0.9 Hz, 1H), 7.88(dd, J=8.9, 2.7 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 6.80 (dd, J=8.9, 0.5Hz, 1H), 4.78 (d, J=4.9 Hz, 1H), 4.49 (s, 1H), 3.94 (d, J=4.7 Hz, 1H),3.81 (s, 3H), 3.12 (t, J=4.8 Hz, 1H), 1.36-1.30 (m, 1H), 1.24-1.19 (m,1H), 0.44-0.38 (m, 1H), 0.23-0.17 (m, 1H).

Example 128:(1S,2S,4R,5R,6R,7S)—N-(6-methoxypyridin-3-yl)-7-(6-(trifluoromethyl)pyridin-2-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.76 min; MS m/z [M+H]⁺ 406.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.10 (s, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.06 (t, J=7.8 Hz, 1H), 7.89 (dd,J=8.9, 2.7 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 6.80(d, J=8.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 1H), 4.49 (s, 1H), 3.87 (d, J=4.8Hz, 1H), 3.81 (s, 3H), 3.66 (t, J=4.9 Hz, 1H), 1.40-1.35 (m, 1H),1.22-1.16 (m, 1H), 0.44-0.39 (m, 1H), 0.22-0.16 (m, 1H).

Example 129:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-fluoropyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.65 min; MS m/z [M+H]⁺ 394.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.26 (s, 1H), 8.64 (d, J=1.6 Hz, 2H), 8.02 (d, J=2.4 Hz,1H), 7.57 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (d,J=4.9 Hz, 1H), 4.41 (s, 1H), 3.68 (d, J=4.6 Hz, 1H), 3.17 (t, J=4.8 Hz,1H), 1.35-1.29 (m, 1H), 1.22-1.16 (m, 1H), 0.45-0.39 (m, 1H), 0.23-0.18(m, 1H).

Example 130:(1S,2S,4R,5R,6R,7S)-7-(pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.56 min; MS m/z [M+H]⁺ 376.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.31 (s, 1H), 9.06 (s, 1H), 8.69 (s, 2H), 8.13 (s, 1H), 7.74 (d, J=8.5Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 4.84 (d, J=4.9Hz, 1H), 4.43 (s, 1H), 3.63 (d, J=4.7 Hz, 1H), 3.20 (t, J=4.8 Hz, 1H),1.37-1.32 (m, 1H), 1.24-1.18 (m, 1H), 0.45-0.39 (m, 1H), 0.23-0.17 (m,1H).

Example 131:(1S,2S,4R,5R,6R,7S)-7-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.40 min; MS m/z [M+H]⁺ 375.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.32 (s, 1H), 8.48 (d, J=5.8 Hz, 2H), 8.13 (s, 1H), 7.74 (d, J=8.5 Hz,1H), 7.55 (t, J=7.9 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.27 (d, J=6.1 Hz,2H), 4.79 (d, J=4.9 Hz, 1H), 4.41 (s, 1H), 3.58 (d, J=4.8 Hz, 1H), 3.11(t, J=4.8 Hz, 1H), 1.36-1.30 (m, 1H), 1.20-1.15 (m, 1H), 0.44-0.40 (m,1H), 0.22-0.17 (m, 1H).

Example 132:(1S,2S,4R,5R,6R,7S)-7-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.46 min; MS m/z [M+H]⁺ 391.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.24 (s, 1H), 8.10 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz,1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 6.52 (s, 2H), 4.73 (d, J=4.9 Hz, 1H),4.25 (s, 1H), 3.34 (d, J=4.0 Hz, 1H), 3.03 (t, J=4.8 Hz, 1H), 1.29-1.24(m, 1H), 1.17-1.11 (m, 1H), 0.41-0.36 (m, 1H), 0.18-0.13 (m, 1H).

Example 133:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-morpholinopyrimidin-5-yl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxamide

LC-MS: Rt=1.72 min; MS m/z [M+H]⁺ 461.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.24 (s, 1H), 8.26 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz,1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.75 (d, J=4.9 Hz, 1H), 4.27 (s, 1H),3.64 (s, 8H), 3.41 (d, J=4.6 Hz, 1H), 3.05 (t, J=4.8 Hz, 1H), 1.31-1.25(m, 1H), 1.18-1.13 (m, 1H), 0.43-0.38 (m, 1H), 0.20-0.14 (m, 1H).

Example 134:(1S,2S,4R,5R,6R,7S)-7-(2-fluoropyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.02,4]octane-6-carboxamide

LC-MS: Rt=1.73 min; MS m/z [M+H]⁺ 393.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.32 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.74 (d, J=8.5 Hz,1H), 7.56 (t, J=8.0 Hz, 1H), 7.44-7.35 (m, 1H), 7.27-7.21 (m, 1H), 7.01(s, 1H), 4.81 (d, J=4.9 Hz, 1H), 4.45 (s, 1H), 3.67 (d, J=4.8 Hz, 1H),3.14 (t, J=4.8 Hz, 1H), 1.36-1.30 (m, 1H), 1.21-1.16 (m, 1H), 0.45-0.38(m, 1H), 0.22-1.16 (m, 1H).

Example 135:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(2-methylpyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

Method B LC-MS: Rt=1.53 min; MS m/z [M+H]⁺ 390.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.26 (s, 1H), 8.55 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.57 (d,J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.80 (d, J=4.9 Hz, 1H),4.37 (s, 1H), 3.56 (d, J=4.7 Hz, 1H), 3.13 (t, J=4.8 Hz, 1H), 2.58 (s,3H), 1.35-1.29 (m, 1H), 1.20-1.15 (m, 1H), 0.44-0.38 (m, 1H), 0.22-0.16(m, 1H).

Example 136:(1S,2S,4R,5R,6R,7S)—N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.28 min; MS m/z [M+H]⁺ 376.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.57 (s, 1H), 8.67 (d, J=5.7 Hz, 2H), 8.50 (d, J=2.4 Hz, 1H), 8.41 (d,J=2.4 Hz, 1H), 7.61 (d, J=5.9 Hz, 2H), 4.87-4.83 (m, 1H), 4.48 (s, 1H),3.76-3.71 (m, 1H), 3.21-3.17 (m, 1H), 1.38-1.33 (m, 1H), 1.28-1.22 (m,1H), 0.45-0.40 (m, 1H), 0.24-0.17 (m, 1H).

Example 137:(1S,2S,4R,5R,6R,7S)—N-(3,4-dichlorophenyl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide

LC-MS: Rt=1.41 min; MS m/z [M+H]⁺ 375.0. H NMR (500 MHz, DMSO-d₆) δ10.25 (s, 1H), 8.47 (d, J=6.1 Hz, 2H), 8.01 (d, J=2.5 Hz, 1H), 7.56 (d,J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.5 Hz, 1H), 7.25 (d, J=6.2 Hz, 2H),4.77 (d, J=4.9 Hz, 1H), 4.40 (s, 1H), 3.56 (d, J=4.8 Hz, 1H), 3.09 (t,J=4.9 Hz, 1H), 1.35-1.29 (m, 1H), 1.21-1.14 (m, 1H), 0.45-0.40 (m, 1H),0.21-0.16 (m, 1H).

Examples 138-154 described infra were synthesized according to theprotocol described for Example 117 using methyl(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1e) and various anilines in Step A and various boronicesters/acids in Step C.

Example 138:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.17 min; MS m/z [M+H]⁺ 393.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.30 (s, 1H), 8.31 (dd, J=2.5, 0.8 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H),7.55 (d, J=8.7 Hz, 1H), 7.54-7.52 (m, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H),7.20 (d, J=8.0 Hz, 1H), 4.96 (d, J=4.7 Hz, 1H), 4.91-4.87 (m, 1H), 4.16(s, 1H), 4.00-3.96 (m, 1H), 3.20 (d, J=5.3 Hz, 1H), 2.94-2.91 (m, 1H),2.12-2.05 (m, 1H), 1.43-1.36 (m, 1H). ˜4:1 mixture of alcoholregioisomers.

Example 139:rac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.46 min; MS m/z [M+H]⁺ 409.0. ˜4:1 mixture of alcoholregioisomers.

Examples 139a and 139b (Corresponding to Peak 1 and Peak 2)(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 139) as a ˜4:1 mixture of alcohol regioisomers by SupercriticalFluid Chromatography using the following conditions afforded thecompounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IB @ 30° C.    -   Mobile Phase: 85% CO₂/15% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=2.40 min. LC-MS: Rt=1.38 min; MS m/z [M+H]⁺409.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.08 (dd, J=5.3, 0.7Hz, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd,J=8.8, 2.5 Hz, 1H), 6.87 (dd, J=5.3, 1.5 Hz, 1H), 6.64 (s, 1H),5.01-4.94 (m, 1H), 4.92-4.84 (m, 1H), 4.21 (s, 1H), 4.00-3.94 (m, 1H),3.82 (s, 3H), 3.20-3.16 (m, 1H), 2.97-2.91 (m, 1H), 2.10-2.03 (m, 1H),1.43-1.36 (m, 1H).

Peak 2: SFC Retention Time=3.59 min. LC-MS: Rt=1.38 min; MS m/z [M+H]⁺409.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.08 (dd, J=5.3, 0.7Hz, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd,J=8.8, 2.5 Hz, 1H), 6.87 (dd, J=5.3, 1.5 Hz, 1H), 6.64 (s, 1H),5.01-4.94 (m, 1H), 4.92-4.84 (m, 1H), 4.21 (s, 1H), 4.00-3.94 (m, 1H),3.82 (s, 3H), 3.20-3.16 (m, 1H), 2.97-2.91 (m, 1H), 2.10-2.03 (m, 1H),1.43-1.36 (m, 1H).

Example 140:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.69 min; MS m/z [M+H]⁺ 447.0. Mixture of alcoholregioisomers.

Example 141:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.37 min; MS m/z [M+H]⁺ 380.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.31 (s, 1H), 9.07 (s, 1H), 8.69 (s, 2H), 7.98 (d, J=2.5 Hz, 1H), 7.56(d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 5.05-4.99 (m, 1H),4.98-4.93 (m, 1H), 4.27 (s, 1H), 4.03-3.97 (m, 1H), 3.31-3.28 (m, 1H),3.05-3.01 (m, 1H), 2.13-2.04 (m, 1H), 1.46-1.35 (m, 1H). ˜6:1 mixture ofalcohol regioisomers.

Example 142:rac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.54 min; MS m/z [M+H]⁺ 397.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.32 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.58-7.54(m, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 7.25-7.22 (m, 1H), 7.01 (s, 1H),5.03-5.01 (m, 1H), 4.94-4.90 (m, 1H), 4.27 (s, 1H), 3.99-3.95 (m, 1H),3.35-3.31 (m, 1H), 3.00-2.95 (m, 1H), 2.10-2.02 (m, 1H), 1.46-1.37 (m,1H). ˜4:1 mixture of alcohol regioisomers.

Examples 142a and 142b (Corresponding to Peak 1 and Peak 2A)(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 142) as a ˜4:1 mixture of alcohol regioisomers by SupercriticalFluid Chromatography using the following conditions afforded thecompounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm AD-H @ 30° C.    -   Mobile Phase: 75% CO₂/25% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.30 min. LC-MS: Rt=1.46 min; MS m/z [M+H]⁺397.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.17 (d, J=5.2 Hz,1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8,2.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.01 (d, J=1.5 Hz, 1H), 5.05-5.00 (m,1H), 4.95-4.89 (m, 1H), 4.27 (s, 1H), 4.01-3.95 (m, 1H), 3.33-3.30 (m,1H), 3.01-2.96 (m, 1H), 2.11-2.03 (m, 1H), 1.46-1.39 (m, 1H).

Peak 2: The second eluting peak isolated using Supercritical FluidChromatography with Retention Time=4.22 min was concentrated andrepurified by Supercritical Fluid Chromatography using the followingconditions to afford the compound listed hereafter:

Method Details:

-   -   Column: 21×250 mm IC @ 30° C.    -   Mobile Phase: 80% CO₂/20% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 2A: First eluting peak. SFC Retention Time=1.21 min. LC-MS: Rt=1.46min; MS m/z [M+H]⁺ 397.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H),8.17 (d, J=5.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H),7.42 (dd, J=8.8, 2.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.01 (d, J=1.5 Hz, 1H),5.05-5.00 (m, 1H), 4.95-4.89 (m, 1H), 4.27 (s, 1H), 4.01-3.95 (m, 1H),3.33-3.30 (m, 1H), 3.01-2.96 (m, 1H), 2.11-2.03 (m, 1H), 1.46-1.39 (m,1H).

Example 143:(1R,2R,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.27 min; MS m/z [M+H]⁺ 395.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.27 (s, 1H), 8.10 (s, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.55 (d, J=8.8 Hz,1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 6.48 (s, 2H), 4.93-4.90 (m, 1H),4.88-4.83 (m, 1H), 4.11 (s, 1H), 3.96-3.93 (m, 1H), 3.03-2.99 (m, 1H),2.91-2.88 (m, 1H), 2.09-2.04 (m, 1H), 1.42-1.34 (m, 1H). ˜5:1 mixture ofalcohol regioisomers.

Example 144:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.39 min; MS m/z [M+H]⁺ 423.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.27 (s, 1H), 8.22 (s, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.55 (d, J=8.8 Hz,1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 4.94-4.91 (m, 1H), 4.89-4.86 (m, 1H),4.12 (s, 1H), 3.97-3.93 (m, 1H), 3.08 (s, 6H), 3.06-3.04 (m, 1H),2.91-2.88 (m, 1H), 2.11-2.06 (m, 1H), 1.41-1.35 (m, 1H). ˜4:1 mixture ofalcohol regioisomers.

Example 145:rac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.63 min; MS m/z [M+H]⁺ 447.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.28 (s, 1H), 8.68 (d, J=5.0 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.73 (s,1H), 7.61-7.59 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz,1H), 5.01-4.99 (m, 1H), 4.97-4.93 (m, 1H), 4.28 (s, 1H), 4.04-3.98 (m,1H), 3.42-3.39 (m, 1H), 3.05-2.99 (m, 1H), 2.13-2.05 (m, 1H), 1.47-1.39(m, 1H). ˜5:1 mixture of alcohol regioisomers.

Examples 145a and 145b (Corresponding to Peak 1 and Peak 2)(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral separation ofrac-(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 145) as a ˜5:1 mixture of alcohol regioisomers by SupercriticalFluid Chromatography using the following conditions afforded thecompounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm AD-H @ 30° C.    -   Mobile Phase: 90% CO₂/10% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=3.44 min. LC-MS: Rt=1.71 min; MS m/z [M+H]⁺447.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.68 (d, J=5.1 Hz,1H), 7.98 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61-7.59 (m, 1H), 7.56 (d,J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.4 Hz, 1H), 5.03-4.99 (m, 1H),4.97-4.93 (m, 1H), 4.27 (s, 1H), 4.04-3.98 (m, 1H), 3.43-3.39 (m, 1H),3.05-2.99 (m, 1H), 2.12-2.05 (m, 1H), 1.47-1.39 (m, 1H).

Peak 2: SFC Retention Time=4.56 min. LC-MS: Rt=1.71 min; MS m/z [M+H]⁺447.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.68 (d, J=5.1 Hz,1H), 7.98 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61-7.59 (m, 1H), 7.56 (d,J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.4 Hz, 1H), 5.03-4.99 (m, 1H),4.97-4.93 (m, 1H), 4.27 (s, 1H), 4.04-3.98 (m, 1H), 3.44-3.38 (m, 1H),3.05-2.99 (m, 1H), 2.12-2.05 (m, 1H), 1.48-1.39 (m, 1H).

Example 146:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.58 min; MS m/z [M+H]⁺ 415.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.32 (s, 1H), 8.01 (d, J=5.2, Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.56 (d,J=8.8 Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 7.38 (t, J=4.9 Hz, 1H),5.09-5.04 (m, 1H), 4.96-4.90 (m, 1H), 4.36 (s, 1H), 4.02-3.96 (m, 1H),3.63-3.58 (m, 1H), 3.02-2.96 (m, 1H), 2.13-2.05 (m, 1H), 1.47-1.40 (m,1H). ˜5:1 mixture of alcohol regioisomers.

Example 147:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2,5-difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.57 min; MS m/z [M+H]⁺ 415.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.30 (s, 1H), 8.18 (d, J=1.3 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.57 (d,J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (dd, J=4.7, 2.1 Hz,1H), 5.08-5.01 (m, 1H), 4.94-4.88 (m, 1H), 4.41 (s, 1H), 4.01-3.97 (m,1H), 3.54-3.50 (m, 1H), 3.02-2.98 (m, 1H), 2.13-2.07 (m, 1H), 1.46-1.37(m, 1H). ˜4:1 mixture of alcohol regioisomers.

Example 148:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.37 min; MS m/z [M+H]⁺ 394.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.28 (s, 1H), 8.56 (s, 2H), 7.97 (dd, J=2.6, 1.0 Hz, 1H), 7.55 (dd,J=8.8, 1.0 Hz, 1H), 7.41 (ddd, J=8.8, 2.5, 1.0 Hz, 1H), 4.99-4.96 (m,1H), 4.94-4.91 (m, 1H), 4.22 (s, 1H), 4.02-3.97 (m, 1H), 3.26-3.22 (m,1H), 3.01-2.97 (m, 1H), 2.57 (s, 3H), 2.12-2.06 (m, 1H), 1.44-1.38 (m,1H). ˜4:1 mixture of alcohol regioisomers.

Example 149:(1R,2R,3S,4R,5S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.29 min; MS m/z [M+H]⁺ 394.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.31 (s, 1H), 7.98-7.96 (m, 1H), 7.80 (d, J=5.2 Hz, 1H), 7.56 (d, J=8.9Hz, 1H), 7.44-7.40 (m, 1H), 6.37-6.30 (m, 2H), 5.84 (s, 2H), 4.95-4.91(m, 1H), 4.85-4.81 (m, 1H), 4.20 (s, 1H), 3.95-3.91 (m, 1H), 3.01-2.98(m, 1H), 2.90-2.86 (m, 1H), 2.07-2.00 (m, 1H), 1.41-1.35 (m, 1H). ˜4:1mixture of alcohol regioisomers.

Example 150:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.25 min; MS m/z [M+H]⁺ 379.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.31 (s, 1H), 8.50-8.47 (m, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 7.28-7.24 (m, 2H), 4.99-4.96 (m,1H), 4.93-4.86 (m, 1H), 4.25 (s, 1H), 4.04-3.97 (m, 1H), 3.25-3.20 (m,1H), 2.99-2.95 (m, 1H), 2.11-2.04 (m, 1H), 1.45-1.38 (m, 1H). ˜4:1mixture of alcohol regioisomers.

Example 151:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-3-(2-fluoropyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.44 min; MS m/z [M+H]⁺ 398.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.34 (s, 1H), 8.65 (d, J=1.7 Hz, 2H), 7.99 (d, J=2.4 Hz, 1H), 7.58-7.54(m, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 5.04-5.01 (m, 1H), 4.97-4.92 (m,1H), 4.27 (s, 1H), 4.02-3.95 (m, 1H), 3.39-3.36 (m, 1H), 3.06-3.02 (m,1H), 2.12-2.04 (m, 1H), 1.46-1.38 (m, 1H). ˜2:1 mixture of alcoholregioisomers.

Example 152:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.95 min; MS m/z [M+H]⁺ 382.1. Mixture of alcoholregioisomers.

Example 153:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.97 min; MS m/z [M+H]⁺ 382.1. ¹H NMR (500 MHz, DMSO-d₆) δ10.40 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.58-7.55 (m, 2H), 7.46 (dd,J=8.8, 2.4 Hz, 1H), 6.06 (d, J=2.2 Hz, 1H), 4.95-4.86 (m, 1H), 4.81-4.76(m, 1H), 4.20 (s, 1H), 3.97-3.90 (m, 1H), 3.75 (s, 3H), 3.27-3.22 (m,1H), 3.21-3.17 (m, 1H), 2.04-1.97 (m, 1H), 1.38-1.32 (m, 1H). ˜4:1mixture of alcohol regioisomers.

Example 154:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.13 min; MS m/z [M+H]⁺ 448.1. ¹H NMR (500 MHz, DMSO-d₆) δ10.33 (s, 1H), 8.93 (s, 2H), 7.98 (d, J=2.4 Hz, 1H), 7.55 (d, J=8.9 Hz,1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 5.09-5.02 (m, 1H), 5.02-4.95 (m, 1H),4.36 (s, 1H), 4.05-3.98 (m, 1H), 3.47-3.42 (m, 1H), 3.12-3.07 (m, 1H),2.15-2.06 (m, 1H), 1.50-1.40 (m, 1H). ˜5:1 mixture of alcoholregioisomers.

Example 155:(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-methoxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 155 described infra was synthesized according to the protocoldescribed for Example 117 using methyl(1R,4S,5S)-3-bromo-5-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylateand methyl(1S,4S,6R)-3-bromo-6-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(Intermediate 1f) and dichloroaniline in Step A and(2-methylpyridin-4-yl)boronic acid in Step C. LC-MS: Rt=1.39 min; MS m/z[M+H]⁺ 407.0. Mixture of alcohol regioisomers.

Examples 156 and 157 (Corresponding to Peak 1 and Peak 2)(1S,2R,3S,4R,5S,6R)—N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideor(1R,2S,3R,4S,5R,6S)—N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (Intermediate1c) using Steps A-E and Step G as in Scheme 5 followed by separation ofenantiomers by chiral chromatography.

Step A: To a solution of the methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (10.0 g, 43.3mmol) in 1:1 acetone/water (200 mL) was added NMO (5.85 g, 43.3 mmol) at0° C. followed by dropwise addition of osmium tetroxide (0.220 g, 0.866mmol) in acetone (15 mL) at 0° C. The resulting reaction mixture wasslowly warmed up to RT and then stirred overnight at RT. The solvent wasconcentrated and the resulting residue was extracted with DCM (100 mL3×). The combined DCM layers were dried over anhydrous Na₂SO₄, filtered,and concentrated. The resulting residue was purified by FCC to affordmethyl 3-bromo-5,6-dihydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate(6.5 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ 5.01 (d, J=1.4 Hz, 1H), 4.75 (d,J=1.4 Hz, 1H), 4.18-3.91 (m, 2H), 3.83 (s, 3H), 3.19 (d, J=6.4 Hz, 1H),3.03 (d, J=6.3 Hz, 1H).

Step B: To a suspension of methyl3-bromo-5,6-dihydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (3.81g, 14.4 mmol) in toluene (150 mL) was added (dimethoxymethyl)benzene(2.63 g, 17.3 mmol) and pTsOH (137 mg, 0.719 mmol). The resultingreaction mixture was heated at 70° C. for 30 min. The reaction mixturewas concentrated and was purified by FCC to afford methyl6-bromo-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxylateas a 2:1 mixture of diastereomers. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (m,1H), 7.51-7.35 (m, 6.5H), 6.37 (s, 1H), 6.04 (s, 0.5H), 5.32 (d, J=1.2Hz, 1H), 5.22 (d, J=1.2 Hz, 0.5H), 5.05 (d, J=1.2 Hz, 1H), 4.95 (d,J=1.2 Hz, 0.5H), 4.77-4.68 (m, 2H), 4.68-4.63 (m, 1H), 3.85 (s, 4.5H).2:1 mixture of diastereomers:

Step C: To a solution of 3,4-dichloroaniline (0.628 g, 3.87 mmol) intoluene (30 mL) was added 2.0 M Me₃Al in toluene (2.10 ml, 4.20 mmol) at0° C. The reaction mixture was stirred for 1 h and then a solution ofmethyl6-bromo-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxylate(1.14 g, 3.23 mmol) in toluene (20 mL) was added dropwise at 0° C. Theresulting reaction mixture was allowed to warm to RT and was stirred atRT overnight. The reaction mixture was quenched with saturated aqueousNH₄Cl and was diluted with EtOAc and water. The aqueous layer wasextracted with EtOAc and the combined organic solvents was washed withwater and brine, dried over anhydrous Na₂SO₄, filtered and concentrated.The resulting residue was purified by FCC to afford(3aS,4S,7S,7aS)-6-bromo-N-(3,4-dichlorophenyl)-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxamide(450 mg, 26%). LC-MS: Rt=1.76 min; MS m/z [M+H]⁺ 482.0.

Step D: To a stirring solution of(3aS,4S,7S,7aS)-6-bromo-N-(3,4-dichlorophenyl)-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxamide(650 mg, 1.307 mmol) In THF (40 mL) and water (10 mL) at 0° C. was addedacetic acid (0.299 mL, 5.23 mmol) followed by the portionwise additionof zinc powder (342 mg, 5.23 mmol). The reaction slurry was allowed towarm to RT and was stirred for 15 minutes. The reaction mixture wasfiltered and neutralized with saturated aqueous sodium bicarbonate to pH7. The mixture was extracted with ethyl acetate and the organic layerwas washed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated. The resulting crude mixture was purified byRP HPLC to afford(3aS,4S,7R,7aR)—N-(3,4-dichlorophenyl)-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxamide,which was used directly for the next step. LC-MS: Rt=1.62 and 1.66 min;MS m/z [M+H]⁺ 404.1.

Step E: A mixture of(3aS,4S,7R,7aR)—N-(3,4-dichlorophenyl)-2-phenyl-3a,4,7,7a-tetrahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxamide(180 mg, 0.445 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (117mg, 0.534 mmol), chloro(1,5-cyclooctadiene)rhodium(I) dimer (11.0 mg,0.022 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (28 mg,0.045 mmol), and potassium carbonate (30.8 mg, 0.223 mmol) was chargedwith 3:1 1,4-dioxane/H₂O (16 mL) and was purged with nitrogen. Theresulting reaction mixture was warmed at 100° C. for 1 h in themicrowave. The reaction mixture was filtered and was purified by RP HPLCto afford(4S,5R,6S,7R)—N-(3,4-dichlorophenyl)-6-(2-methylpyridin-4-yl)-2-phenylhexahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxamide.LC-MS: Rt=1.43 min; MS m/z [M+H]⁺ 497.2.

Step G: To a solution of(4S,5R,6S,7R)—N-(3,4-dichlorophenyl)-6-(2-methylpyridin-4-yl)-2-phenylhexahydro-4,7-epoxybenzo[d][1,3]dioxole-5-carboxamide(133 mg, 0.267 mmol) and 1,2,3,4,5-pentamethylbenzene (119 mg, 0.802mmol) in DCM (3.0 mL) was added dropwise 1.0 M BCl₃ in DCM (1.34 mL,1.34 mmol) at 0° C. The resulting reaction mixture was stirred for 1 hat 0° C. and then was allowed to warm to RT and was stirred for 1 h. Thereaction mixture was quenched with saturated aqueous NaHCO₃, and theaqueous layer was extracted with DCM. The combined organic layers weredried over Na₂SO₄, filtered and concentrated to get the crude product,which was purified by HPLC to affordrac-(1S,2R,3S,4R,5S,6R)—N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideas a mixture of enantiomers. LC-MS: Rt=1.06 min; MS m/z [M+H]⁺ 409.1.

Chiral separation ofrac-(1S,2R,3S,4R,5S,6R)—N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideby Supercritical Fluid Chromatography using the following conditionsafforded the compounds listed hereafter:

Method Details:

-   -   Column: 21×250 mm IA @ 30° C.    -   Mobile Phase: 75% CO₂/25% MeOH+0.5% isopropylamine    -   Detection: UV @ 220 nm    -   Flow: 2 mL/min

Peak 1: SFC Retention Time=1.47 min. LC-MS: Rt=1.07 min; MS m/z [M+H]⁺409.1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.40 (d, J=5.3 Hz,1H), 8.01 (d, J=2.4 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.48 (dd, J=8.8,2.5 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.16 (dd, J=5.5, 1.7 Hz, 1H), 4.98(brs, 1H), 4.83 (brs, 1H), 4.61 (dd, J=5.6, 1.6 Hz, 1H), 4.23 (d, J=1.5Hz, 1H), 3.92 (q, J=4.6 Hz, 2H), 3.00 (t, J=5.5 Hz, 1H), 2.47 (s, 3H).

Peak 2: SFC Retention Time=2.54 min. LC-MS: Rt=1.07 min; MS m/z [M+H]⁺409.2.

Examples 158-163 described infra were synthesized according to theprotocol described for Example 156 using methyl3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (Intermediate1c) and various anilines in Step C and various boronic esters/acids inStep E.

Example 158:(1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.05 min; MS m/z [M+H]⁺ 409.2.

Example 159:(1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.07 min; MS m/z [M+H]⁺ 395.2.

Example 160:(1S,2R,3S,4R,5S,6R)—N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.08 min; MS m/z [M+H]⁺ 395.1.

Example 161:(1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-N-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.85 min; MS m/z [M+H]⁺ 410.2.

Example 162:(1S,2R,3S,4R,5S,6R)—N-(5,6-dichloropyridin-3-yl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.96 min; MS m/z [M+H]⁺ 410.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.73 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.40-8.36 (m, 2H), 7.18 (s, 1H),7.12 (dd, J=5.3, 1.7 Hz, 1H), 4.94 (s, 2H), 4.63-4.58 (m, 1H), 4.24-4.21(m, 1H), 3.96-3.90 (m, 2H), 3.35-3.28 (m, 1H), 3.03-2.97 (m, 1H), 2.45(s, 3H).

Example 163:(1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.92 min; MS m/z [M+H]⁺ 424.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.63 (s, 1H), 8.78 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.5 Hz, 1H), 8.39 (d,J=5.5 Hz, 1H), 7.22 (s, 1H), 7.16 (dd, J=5.4, 1.7 Hz, 1H), 4.94 (s, 1H),4.85 (s, 1H), 4.63-4.58 (m, 1H), 4.24-4.21 (m, 1H), 3.97-3.90 (m, 2H),3.36-3.32 (m, 1H), 3.05-2.99 (m, 1H), 2.59-2.56 (m, 3H), 2.46 (s, 3H).

Example 164:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(5a, wherein R₂=3,4-dichlorophenyl and Ar=6-methylpyridin-3-yl, Example138) using Step A as in Scheme 6.

Step A: To a stirring solution of(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(25 mg, 0.064 mmol) in DCM (1 mL) at room temperature was addedXtalfluor-E (22 mg, 0.095 mmol) and triethylamine trihydrofluoride(0.021 mL, 0.127 mmol). The reaction mixture was stirred for 16 h, wascooled to 0° C. and quenched with saturated aqueous sodium bicarbonatesolution. The crude mixture was extracted with DCM 3×. The combinedorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude compound was purified by FCC to afford(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.46 min; MS m/z [M+H]⁺ 395.0. ¹H NMR (500 MHz, DMSO-d₆) δ10.62 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.59-7.56(m, 2H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 5.27 (d,J=71.0 Hz, 1H), 4.85-4.77 (m, 1H), 3.81-3.76 (m, 1H), 3.15-3.13 (m, 1H),3.12-3.09 (m, 1H), 2.44 (s, 3H), 1.99-1.91 (m, 2H). >20:1 mixture ofalcohol regioisomers.

Example 165:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 165 was synthesized according to the protocol described forExample 164 using(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(5a, wherein R₂=3,4-dichlorophenyl and Ar=2-methoxypyridin-4-yl, Example139) in Step A. LC-MS: Rt=1.74 min; MS m/z [M+H]⁺ 411.0. ¹H NMR (500MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.13-8.12 (m, 1H), 7.99 (d, J=2.4 Hz,1H), 7.58 (d, J=8.8 Hz, 1H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 6.95-6.92 (m,1H), 6.75 (s, 1H), 5.31-5.13 (m, 1H), 4.84-4.81 (m, 1H), 3.85 (s, 3H),3.80-3.76 (m, 1H), 3.25-3.21 (m, 1H), 3.11-3.08 (m, 1H), 1.97-1.91 (m,2H). ˜2:1 mixture of alcohol regioisomers.

Example 166:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-(dimethylamino)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(5a, wherein R₂=3,4-dichlorophenyl and Ar=2-methylpyridin-4-yl, Example77) using Steps B and C as in Scheme 6.

Step B: To a stirring solution of(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(200 mg, 0.509 mmol) in THF (5 mL) at RT was added Dess-Martin reagent(431 mg, 1.02 mmol) and the reaction was stirred at room temperature for16 h. The reaction mixture was diluted with EtOAc, washed with sat. aq.NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated. Theresulting residue was purified by FCC to afford(1R,2R,3S,4R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.22 min; MS m/z [M+H]⁺ 391.0.

Step C: To a stirring solution of(1R,2R,3S,4R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7-oxabicyclo[2.2.1]heptane-2-carboxamide(20 mg, 0.051 mmol) in DCM (2 mL) was added one drop of acetic acid anddimethylamine in THF (0.153 mL, 0.307 mmol). The reaction was cooled to0° C. and sodium borohydride (4 mg, 0.102 mmol) was added. The reactionwas stirred at RT for 30 minutes, then was warmed at 50° C. for 2 h. Thereaction mixture was cooled to room temperature and was filtered and thefiltrate was concentrated. The crude compound was purified by RP HPLC toafford(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-(dimethylamino)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.12 min; MS m/z [M+H]⁺ 420.1. ¹H NMR (400 MHz, DMSO-d₆) δ10.21 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.55 (d,J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 2.5 Hz, 1H), 7.12 (s, 1H), 7.06 (d,J=5.3 Hz, 1H), 4.94-4.87 (m, 1H), 4.48-4.42 (m, 1H), 4.13-4.08 (m, 1H),3.10-3.04 (m, 1H), 2.43 (s, 3H), 2.42-2.35 (m, 1H), 2.12 (s, 6H),1.89-1.79 (m, 1H), 1.48-1.40 (m, 1H). >20:1 mixture of alcoholregioisomers.

Examples 167-177 described infra were synthesized according to theprotocol described for Example 166 using intermediate 5a and variousamines in Step C.

Example 167:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-(methylamino)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.10 min; MS m/z [M+H]⁺ 406.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.44 (s, 1H), 8.37-8.32 (m, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8Hz, 1H), 7.45 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (s, 1H), 7.08 (dd, J=5.2,1.7 Hz, 1H), 4.90-4.84 (m, 1H), 4.49-4.44 (m, 1H), 3.99-3.95 (m, 1H),3.16 (s, 1H), 3.15-3.11 (m, 1H), 3.09-3.02 (m, 1H), 2.43 (s, 3H), 2.28(s, 3H), 1.99-1.89 (m, 1H), 1.28-1.20 (m, 1H). >20:1 mixture of alcoholregioisomers.

Example 168:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-((2-hydroxyethyl)amino)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.06 min; MS m/z [M+H]⁺ 436.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.47 (s, 1H), 8.35 (dd, J=5.1, 0.7 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H),7.56 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (d, J=1.7 Hz,1H), 7.08 (dd, J=5.2, 1.7 Hz, 1H), 4.87-4.84 (m, 1H), 4.60-4.54 (m, 1H),4.48-4.44 (m, 1H), 4.01-3.97 (m, 1H), 3.50-3.43 (m, 2H), 3.22-3.11 (m,3H), 2.59-2.53 (m, 2H), 2.44 (s, 3H), 2.02-1.93 (m, 1H), 1.28-1.20 (m,1H). >20:1 mixture of alcohol regioisomers.

Example 169:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-((tetrahydro-2H-pyran-4-yl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.16 min; MS m/z [M+H]⁺ 476.2. Mixture of alcoholregioisomers.

Example 170:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-(((1r,3R)-3-hydroxycyclobutyl)amino)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.07 min; MS m/z [M+H]⁺ 462.2. Mixture of alcoholregioisomers.

Example 171:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-(methylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.26 min; MS m/z [M+H]⁺ 410.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.33 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.57 (d,J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.4 Hz, 1H), 7.28-7.25 (m, 1H), 7.03 (s,1H), 4.93-4.86 (m, 1H), 4.56-4.51 (m, 1H), 4.14-4.09 (m, 1H), 3.33-3.30(m, 1H), 3.16-3.12 (m, 1H), 3.10-3.02 (m, 1H), 2.28 (s, 3H), 1.98-1.90(m, 1H), 1.27-1.21 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 172:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-(dimethylamino)-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.25 min; MS m/z [M+H]⁺ 424.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.20 (s, 1H), 8.17 (d, J=5.3 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.56 (d,J=8.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.25-7.21 (m, 1H), 7.00 (s, 1H),4.97-4.92 (m, 1H), 4.55-4.51 (m, 1H), 4.25-4.18 (m, 1H), 3.13-3.08 (m,1H), 2.43-2.37 (m, 1H), 2.12 (s, 6H), 1.90-1.81 (m, 1H), 1.47-1.39 (m,1H). >20:1 mixture of alcohol regioisomers.

Example 173:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-((2-hydroxyethyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.21 min; MS m/z [M+H]⁺ 440.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.36 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.57 (d,J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.4 Hz, 1H), 7.28-7.24 (m, 1H), 7.03 (d,J=1.4 Hz, 1H), 4.91-4.84 (m, 1H), 4.59-4.55 (m, 1H), 4.53 (d, J=4.6 Hz,1H), 4.13 (d, J=5.5 Hz, 1H), 3.50-3.43 (m, 2H), 3.36-3.31 (m, 1H),3.22-3.13 (m, 2H), 2.62-2.52 (m, 2H), 2.04-1.94 (m, 1H), 1.29-1.22 (m,1H). >20:1 mixture of alcohol regioisomers.

Example 174:(1R,2R,3S,4R,5R)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-(methylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.11 min; MS m/z [M+H]⁺ 411.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.60 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.17 (d,J=5.2 Hz, 1H), 7.29-7.25 (m, 1H), 7.04 (s, 1H), 4.94-4.90 (m, 1H),4.58-4.51 (m, 1H), 4.17-4.12 (m, 1H), 3.33-3.29 (m, 1H), 3.20-3.16 (m,1H), 3.10-3.04 (m, 1H), 2.27 (s, 3H), 1.99-1.91 (m, 1H), 1.29-1.22 (m,1H). >20:1 mixture of alcohol regioisomers.

Example 175:(1R,2R,3S,4R,5R)—N-(5,6-dichloropyridin-3-yl)-5-(dimethylamino)-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.13 min; MS m/z [M+H]⁺ 425.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.46 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.18 (d,J=5.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.02-7.00 (m, 1H), 4.98-4.94 (m, 1H),4.57-4.53 (m, 1H), 4.25-4.19 (m, 1H), 3.17-3.11 (m, 1H), 2.44-2.36 (m,1H), 2.12 (s, 6H), 1.91-1.81 (m, 1H), 1.48-1.38 (m, 1H). >20:1 mixtureof alcohol regioisomers.

Example 176:(1R,2R,3S,4R,5R)—N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-((2-hydroxyethyl)amino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.08 min; MS m/z [M+H]⁺ 441.2. ¹H NMR (400 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.18 (d,J=5.2 Hz, 1H), 7.28-7.25 (m, 1H), 7.03 (s, 1H), 4.92-4.86 (m, 1H),4.60-4.53 (m, 2H), 4.15 (d, J=5.6 Hz, 1H), 3.50-3.43 (m, 2H), 3.35-3.29(m, 1H), 3.24-3.15 (m, 2H), 2.63-2.52 (m, 2H), 2.04-1.94 (m, 1H), 1.26(dd, J=12.8, 4.7 Hz, 1H). >20:1 mixture of alcohol regioisomers.

Example 177:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-morpholino-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.15 min; MS m/z [M+H]⁺ 462.1. Mixture of alcoholregioisomers.

Example 178:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-5-methyl-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from single enantiomer(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(5a, wherein R₂=3,4-dichlorophenyl and Ar=2-methylpyridin-4-yl, Example77a) using Steps B and D as in Scheme 6.

Step B: To a stirring solution of(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(200 mg, 0.509 mmol) in THF (5 mL) at RT was added Dess-Martin reagent(431 mg, 1.017 mmol) and the reaction was stirred at room temperaturefor 16 h. The reaction mixture was diluted with EtOAc, washed with sat.aq. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated. Theresulting residue was purified by FCC to afford(1R,2R,3S,4R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.22 min; MS m/z [M+H]⁺ 391.0.

Step D: A solution of(1R,2R,3S,4R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7-oxabicyclo[2.2.1]heptane-2-carboxamide(10.4 mg, 0.027 mmol) in THF (0.5 mL) at RT was treated with MeMgBr, 3.0M in diethyl ether (35.4 μl, 0.106 mmol) and was stirred for 2 h.Additional MeMgBr, 3.0 M in diethyl ether (35.4 μl, 0.106 mmol) wasadded and the reaction was stirred at RT for 16 h. The reaction mixturewas quenched with sat. aq. NH₄Cl, diluted with EtOAc, washed with waterand brine, dried (Na₂SO₄), filtered, and concentrated. The resultingresidue was purified by FCC to afford(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-5-methyl-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.27 min; MS m/z [M+H]⁺ 407.2.

Example 179:(1S,2S,3R,4S,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-5-methyl-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 179 was synthesized according to the protocol described forExample 178 using single enantiomer (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 77c). LC-MS: Rt=1.27 min; MS m/z [M+H]⁺ 407.2. >20:1 mixture ofalcohol regioisomers.

Example 180:(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Title compound was prepared from single enantiomer(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(5a, wherein R₂=3,4-dichlorophenyl and Ar=2-methylpyridin-4-yl, Example77a) using Steps B and E as in Scheme 6.

Step B: To a stirring solution of(1R,2R,3S,4R,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(200 mg, 0.509 mmol) in THF (5 mL) at RT was added Dess-Martin reagent(431 mg, 1.017 mmol) and the reaction was stirred at room temperaturefor 16 h. The reaction mixture was diluted with EtOAc, washed with sat.aq. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated. Theresulting residue was purified by FCC to afford(1R,2R,3S,4R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.22 min; MS m/z [M+H]⁺ 391.0.

Step E: A solution of1R,2R,3S,4R)—N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7-oxabicyclo[2.2.1]heptane-2-carboxamide(18 mg, 0.046 mmol) in THF (1 mL) at RT was treated with NaBH₄ (6.96 mg,0.184 mmol) and was stirred at RT for 18 h. The reaction mixture wasdiluted with sat. aq. NaHCO₃ and was extracted with EtOAc. The organiclayer was washed with brine, dried (Na₂SO₄), filtered, and concentrated.The resulting residue was purified by FCC to afford(1R,2R,3S,4R,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide.LC-MS: Rt=1.20 min; MS m/z [M+H]⁺ 393.1. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.59 (s, 1H), 8.35 (dd, J=5.2, 0.8 Hz, 1H), 7.89 (dd,J=2.2, 0.6 Hz, 1H), 7.46-7.38 (m, 2H), 7.18-7.16 (m, 1H), 7.10 (dd,J=5.2, 1.7 Hz, 1H), 4.87-4.79 (m, 1H), 4.42-4.34 (m, 1H), 4.33-4.24 (m,1H), 4.17-4.13 (m, 1H), 3.65-3.55 (m, 1H), 3.15-3.07 (m, 1H), 2.46 (s,3H), 2.12-2.02 (m, 1H), 1.54-1.46 (m, 1H). >20:1 mixture of alcoholregioisomers.

Example 181:(1S,2S,3R,4S,5S)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Example 181 was synthesized according to the protocol described forExample 180 using single enantiomer (1S,2S,3R,4S,5R)—N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(Example 77c). LC-MS: Rt=1.20 min; MS m/z [M+H]⁺ 393.1. ¹H NMR (400 MHz,Acetonitrile-ds) δ 8.60 (s, 1H), 8.36-8.34 (m, 1H), 7.89 (dd, J=2.2, 0.6Hz, 1H), 7.46-7.39 (m, 2H), 7.17 (s, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H),4.86-4.81 (m, 1H), 4.42-4.37 (m, 1H), 4.31-4.24 (m, 1H), 4.17-4.11 (m,1H), 3.63-3.57 (m, 1H), 3.15-3.09 (m, 1H), 2.46 (s, 3H), 2.11-2.01 (m,1H), 1.54-1.45 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 182. The incorporation of a 5S-hydroxyl group into theoxabicycle core reduces the CYP3A4 inhibition and the intrinsicclearance in both rat and human liver microsomes of the compounds, asshown in Table 1.

TABLE 1

rat liver 466 7 243 11 microsomes CL_(int) (μL/min/mg) human liver 202 738 7 microsomes CL_(int) (μL/min/mg) CYP3A4 inh. 6 >25 5 20 (μM)

Biological Assays

The compounds of the present invention were evaluated in the followingassays: (1) the Collagen type II assay to measure chondrogenicdifferentiation; (2) the Alkaline Phosphatase (ALP) activity assay todetermine the ability of the compounds to prevent chondrocytehypertrophy in normal human articular chondrocytes (NHACs) and C3H10T1/2cell line; and (3) calcium flux assay.

TABLE 2 Reagents used for experimentation Catalog Dilution/ DescriptionCompany number Concentration Collagenase, Type II Worthington CLS-2 0.2mg/ml Biochemicals Anti-type II collagen Abcam 3092 1:500  Anti-mouse647 Life Technologies A-21235 1:5000 Bovine Serum Albumin (BSA) TritonX-100 Hoescht 33342 Life Technologies H3570 1:1000 Fast Blue RR SaltSigma F0500-25G  0.024% w/v Naphthol AS-MX Sigma 855-20ML    4% v/vPhosphate Alkaline Solution Calcium 5 dye Molecular Devices R8186 100ml/vial Probenecid Sigma P8761-100G 5 mM HEPES Hyclone SH30237.01 10 mM 

Cell Culture

Normal human articular chondrocytes (NHACs) were purchased fromPromoCell (Heidelberg, Germany) and grown in Chondrocyte Growth Medium(CGM; Lonza, Walkersville, Md.). C3H10T1/2 cell line (clone 8) waspurchased from ATCC (Manassas, Va.) and grown in DMEM/High glucosesupplemented with 10% FBS and antibiotic/antimycotic (ThermoFisherscientific, Waltham, Mass.). Human chondrogenic progenitor cell (CPCs)were derived from human primary articular chondrocytes (Lonza,Walkersville, Md.) which were separated into single cells, clonallygrown in Mesenchymal Stem Cell Growth Medium (MSCGM; Lonza, WalkersvilleMd.) and validated as mesenchymal progenitors through chondrogenic,osteogenic and adipogenic differentiation. The cells were FACS sortedand proven to be >98% positive for CD166 and CD105. CPCs were culturedup to 20 passages with no alteration in the cell profile, growth ordifferentiation rates identified.

Collagen Type II Assay and Quantitation

To initiate chondrogenesis in primary CPCs, 8000 cells were plated/wellin a Costar 96 well plate in MSCGM. After 24 hours the MSCGM was removedand replaced with DMEM containing 1% FBS. The test compound was thenadded to each well at the indicated dose. The cultures were grown at 37°C. for 18 days. A media supplement of an additional 50 μl of DMEMcontaining 1% FBS was given 10 days after chondrogenic induction.

To detect the presence of Collagen type II, hCPCs were fixed with 10%formalin for 20 minutes, permeablized with PBS containing 0.1% tritonX-100, 0.2 mg/ml of Collagenase 2 for 10 minutes, blocked with PBScontaining 5% BSA for 1 hr at room temperature, followed by incubationwith primary antibody (anti-type II collagen antibody) in PBS containing1% BSA overnight at 4° C. Cells were washed 3 times with PBS andincubated with fluorophore-conjugated secondary antibody and Hoechst dyefor 1 hour at room temperature, followed by washing with PBS for 3times.

The total intensity of staining was imaged by fluorescent microscopyand/or quantified by high content imagining with the ImageXpress Micro(Molecular Devices, Sunnyvale, Calif.). Data analyses were performedwith the customized multiwavelength cell-scoring application.

Alkaline Phosphatase Staining and Quantitation in NHACs

To initiate differentiation in NHACs, 16,000 cells were plated/well inCostar 96 well plate in CGM media (Lonza). After 24 hours the MSCGM wasremoved and replaced with DMEM containing 1% FBS. The test compound wasthen added to each well at the indicated dose. The cultures were grownat 37° C. for 10 days.

To detect the presence of hypertrophic cells, NHACs were fixed with 10%formalin and Hoeschst dye for 20 minutes, rinsed in PBS, then stainedwith Fast Blue RR Salt with Naphthol AS-MX Phosphate Alkaline Solution.Once cells were observed to turn blue, after approximately 2 hours at37° C., they were washed with PBS three times.

The total intensity of staining was imaged by fluorescent microscopy,using the 651 wavelength, and/or quantified by high content imaginingwith the ImageXpress Micro (Molecular Devices, Sunnyvale, Calif.). Dataanalyses were performed with the customized multiwavelength cell-scoringapplication.

Alkaline Phosphatase Staining and Quantitation in C3H10T1/2

To initiate differentiation in C3H10T1/2, Clone 8 (ATCC cat #CCL-226),4,000 cells were plated/well in 384 Perkin Elmer CellCarrier Ultra platein DMEM/High glucose (HyClone cat #SH30022.01) containing 10% FBS and 1×Antibiotic/Antimycotic (HyClone cat #SV30079.01). After 24 hours thetest compound was then added to each well at the indicated dose. Thecultures were grown at 37° C. for 6 days.

To detect the presence of hypertrophic cells, C3H10T1/2 were fixed with4% paraformaldehyde and Hoeschst dye for 20 minutes, rinsed in PBS, thenstained with Fast Blue RR Salt with Naphthol AS-MX Phosphate AlkalineSolution. Once cells were observed to turn blue, after approximately 3hours at 37° C., they were washed with PBS six times.

The ALP staining was imaged by fluorescent microscopy, using the 561wavelength, and/or quantified by high content imagining with theImageXpress Micro Confocal (Molecular Devices, Sunnyvale, Calif.). Dataanalyses were performed with the customized multiwavelength cell-scoringapplication looking at the number of ALP positive cells per well.

Calcium Flux assay and Quantitation

NHACs were plated in 1536 Greiner plate at 2000 cells/well in 4 ulvolume. 24 hours later, 4 ul of Calcium 5 dye solution (Hank's BalancedSalt/HEPES buffer containing 5 mM of Probenecid) was then added andincubated for 1 hour at room temperature. Fluorescence readings atexcitation wavelength of 470-495 nm and emission wavelength of 515-575nm were done using FLIPR high-throughput screening system (MolecularDevices, Sunnyvale, Calif.). The test compound was then added to eachwell at the indicated dose. Signal was measured prior compound dispenseand after using a first interval of 1 second for 60 reads and secondinterval of 3 second for 20 reads. Data was analyzed using MolecularDevices ScreenWorks® Software.

The activity of the compounds of the present invention in the followingassays are summarized in Table 3. Legend: (A) calcium flux assay; (B)collagen Type II assay; (C) alkaline phosphatase assay in NHAC; and (D)alkaline phosphatase assay in C3H10T1/2.

TABLE 3 (A) (B) (C) (D) EC₅₀ EC₅₀ IC₅₀ IC₅₀ μM (% μM (% μM (% μM (% ExNo. Efficacy) Efficacy) Efficacy) Efficacy)  1(1S,2S,4R,5R,6S,7S)-N-(5,6- 3.4 (164) dichloropyridin-3-yl)-7-(2-methoxypyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 2 rac-(1S,2S,4R,5R,6S,7S)-N-(6- >50 (0) methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 3 (1S,2S,4R,5R,6S,7S)-N-(6- 0.30 (45) methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 4 (1R,2R,4S,5S,6R,7R)-N-(6- >50 (0) methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 5 (1R,2S,3S,4R,5S)-N-(4,5- >50 (28) dichloropyridin-2-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  6(1R,2S,3S,4R,5S)-N-(5-chloro-6- >50 (18)methylpyridin-3-yl)-5-hydroxy-3- (2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  7 (1R,2S,3S,4R,5S)-N-(5,6- >50(17) dichloropyridin-3-yl)-5-hydroxy- 3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  8 (1S,2R,3R,4S,5R)-N-(5,6- >50(0) dichloropyridin-3-yl)-5-hydroxy- 3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  9(1R,2S,3S,4R,5S)-5-hydroxy-3- >50 (50) >31 (62) >20 (16)(2-methylpyridin-4-yl)-N-[3- (trifluoromethyl)phenyl]-7-oxabicyclo[2.2.1]heptane-2- carboxamide  10(1S,2S,3S,4S,6R)-6-hydroxy-3- >50 (0) (2-methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  11rac-(1R,2S,3S,4R,5S)-N-(5,6- >50 (0) dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  11a(1R,2S,3S,4R,5S)-N-(5,6- >50 (55) dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  12rac-(1R,2S,3S,4R,5S)-5- >50 (27) hydroxy-3-(pyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  12a(1R,2S,3S,4R,5S)-5-hydroxy-3- 0.27 (98) 2.9 (91) 48 (65) >20 (6)(pyridin-4-yl)-N-[3- (trifluoromethyl)phenyl]-7-oxabicyclo[2.2.1]heptane-2- carboxamide  13(1S,2S,3S,4S,6R)-6-hydroxy-3- >50 (22) (pyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  14(1R,2S,3S,4R,5R)-N-(3,4- 4.5 (68) dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  15(1R,2S,3S,4R,5R)-5-fluoro-N-(6- 8.3 (115) methoxypyridin-3-yl)-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  16(1R,2S,3S,4R,5R)-5-fluoro-3-(2- >50 (0) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  17(1R,2S,3S,4R,5S)-N-(3,4- 21 (105) dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  18(1R,2S,3S,4R,5S)-5-fluoro-3-(2- >50 (0) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  19(1R,2S,3S,4R,5S)-N-(5,6- >50 (0) dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  20(1R,2S,3S,4R,5S)-N-(3,4- 25 (258) dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  21(1R,2S,3S,4R,5S)-3-(2- >50 (5) aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-fluoro-7- oxabicyclo[2.2.1]heptane-2- carboxamide  22(1R,2S,3S,4R,5S)-N-(3,4- 27 (159) dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  23(1R,2S,3S,4R,5S)-N-(3,4- 4.2 (128) dichlorophenyl)-5-fluoro-3-(2-fluoropyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  24rac-(1S,2S,4R,5R,6S,7S)-N- >50 (54) (3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 24a (1S,2S,4R,5R,6S,7S)-N-(3,4- 6.1 (99) 0.78 (29) 30 (100) >20 (28)dichlorophenyl)-7-(2- methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  24b(1R,2R,4S,5S,6R,7R)-N-(3,4- >50 (0) dichlorophenyl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 25 (1S,2S,4R,5R,6S,7S)-N-(3,4- 11 (71) dichlorophenyl)-7-(2-methoxypyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 26 (1S,2S,4R,5R,6S,7S)-N-(3,4- 17 (52) dichlorophenyl)-7-(2-fluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 27 (1S,2S,4R,5R,6S,7S)-7-(2- 23 (54) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide  28 (1S,2S,4R,5R,6S,7S)-N-(3,4- 13 (120) 34 (71) >20 (48)dichlorophenyl)-7-(pyrimidin-5- yl)-8-oxatricyclo[3.2.1.0^(2,4)}]octane-6- carboxamide  29(1R,2R,4S,5S,6R,7R)-N-(3,4- 23 (167) dichlorophenyl)-7-(pyrimidin-5-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  30(1S,2S,4R,5R,6S,7S)-N-(3,4- >50 (6) dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 31 (1R,2R,4S,5S,6R,7R)-N-(3,4- 10 (133) dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 32 (1S,2S,4R,5R,6S,7S)-N-(5,6- 13 (143) dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 33 (1S,2S,4R,5R,6S,7S)-N-(6- 4.6 (49) methoxypyridin-3-yl)-7-(pyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  34(1S,2S,4R,5R,6S,7S)-7-(2,3- >50 (3) difluoropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 35 (1S,2S,4R,5R,6S,7S)-N-(6- >50 (0) methoxypyridin-3-yl)-7-[6-(trifluoromethyl)pyridin-2-yl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide  36 (1S,2S,4R,5R,6S,7S)-N-(3,4- 8.6 (124)dichlorophenyl)-7-(2- fluoropyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)}]octane-6- carboxamide  37(1S,2S,4R,5R,6S,7S)-7- >50 (26) (pyrimidin-5-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide  38 (1S,2S,4R,5R,6S,7S)-7-(pyridin- 9.9 (36) 4-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide  39 (1S,2S,4R,5R,6S,7S)-7-(2- 0.53 (40)aminopyrimidin-5-yl)-N-(3,4- dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  40(1S,2S,4R,5R,6S,7S)-N-(3,4- >50 (37) dichlorophenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 41 (1S,2S,4R,5R,6S,7S)-7-(2- 24 (121) fluoropyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide  42 (1S,2S,4R,5R,6S,7S)-N-(3,4- 18 (57)dichlorophenyl)-7-(2- methylpyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  43rac-(1S,2S,4R,5R,6S,7S)-N- >50 (168) (5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  43a(1S,2S,4R,5R,6S,7S)-N-(3,4- >50 (0) dichlorophenyl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  43b(1R,2R,4S,5S,6R,7R)-N-(5,6- >50 (3) dichloropyridin-3-yl)-7-(pyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  44(1S,2S,4R,5R,6S,7S)-N-(3,4- >50 (0) dichlorophenyl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  45(1S,2S,4R,5R,6S,7S)-N-(5,6- 14 (32) dichloropyridin-3-yl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 46 (1R,2R,4S,5S,6R,7R)-N-(5,6- >50 (0) dichloropyridin-3-yl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 47 rac-(1R,2S,3S,4R,5S)-N-(3,4- 7.8 (38) dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  47a(1R,2S,3S,4R,5S)-N-(3,4- >50 (68) 2.1 (82) 33 (88) >20 (23)dichlorophenyl)-5-hydroxy-3- (pyridin-4-yl)-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  48 (1R,2S,3S,4R,5S)-N-(3,4- 22(80) dichlorophenyl)-5-hydroxy-3-(6- methylpyridin-3-yl)-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  49rac-(1R,2S,3S,4R,5S)-N-(3,4- 11 (77) dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  49a(1R,2S,3S,4R,5S)-N-(3,4- 0.84 (53) dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  49b(1S,2R,3R,4S,5R)-N-(3,4- >50 (31) dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  50(1R,2S,3S,4R,5S)-N-(3,4- 21 (308) dichlorophenyl)-5-hydroxy-3-[6-(trifluoromethyl)pyridin-2-yl]-7- oxabicyclo[2.2.1.]heptane-2-carboxamide  51 (1R,2S,3S,4R,5S)-N-(3,4- >50 (0)dichlorophenyl)-5-hydroxy-3- (pyrimidin-5-yl)-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  52rac-(1R,2S,3S,4R,5S)-N-(3,4- >50 (4) dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1.]heptane-2-carboxamide  52a (1R,2S,3S,4R,5S)-N-(3,4- >50 (96) 0.49 (80) 17 (71) >20(36) dichlorophenyl)-3-(2- fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  52b(1S,2R,3R,4S,5R)-N-(3,4- >50 (1) dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1.]heptane-2-carboxamide  53 rac-(1R,2S,3S,4R,5S)-N-(3,4- >50 (43)dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  53a(1R,2S,3S,4R,5S)-N-(3,4- >50 (12) 13 (44) 31 (83) >20 (0)dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  53b(1S,2R,3R,4S,5R)-N-(3,4- >50 (119) dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  54rac-(1R,2S,3S,4R,5S)-N-(3,4- >50 (22) >20 (35)dichlorophenyl)-5-hydroxy-3-[2- (trifluoromethyl)pyridin-4-yl]-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  54a (1R,2S,3S,4R,5S)-N-(3,4-3.5 (45) >20 (35) dichlorophenyl)-5-hydroxy-3-[2-(trifluoromethyl)pyridin-4-yl]-7- oxabicyclo[2.2.1.]heptane-2-carboxamide  54b (1S,2R,3R,4S,5R)-N-(3,4- >50 (16) >20 (46)dichlorophenyl)-5-hydroxy-3-[2- (trifluoromethyl)pyridin-4-yl]-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  55(1R,2S,3S,4R,5S)-N-(3,4- >50 (0) dichlorophenyl)-3-[2-(dimethylamino)pyrimidin-5-yl]-5- hydroxy-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  56(1R,2S,3S,4R,5S)-N-(3,4- >50 (0) dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-5-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  57(1R,2S,3S,4R,5S)-3-(2- >50 (56) aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7- oxabicyclo[2.2.1.]heptane-2- carboxamide 58 (1R,2S,3S,4R,5S)-N-(3,4- >50 (0) dichlorophenyl)-3-(2,5-difluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1.]heptane-2-carboxamide  59 (1R,2S,3S,4R,5S)-N-(3,4- 1.2 (254)dichlorophenyl)-3-(2,3- difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  60 (1R,2S,3S,4R,5S)-3-(2- >50(2) aminopyrimidin-5-yl)-N-(3,4- dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  61(1R,2S,3S,4R,5S)-N-(3,4- >50 (24) dichlorophenyl)-3-(2-fluoropyrimidin-5-yl)-5-hydroxy- 7-oxabicyclo[2.2.1.]heptane-2-carboxamide  62 (1R,2S,3S,4R,5S)-N-(3,4- 8.2 (61)dichlorophenyl)-5-hydroxy-3-[2- (trifluoromethyl)pyrimidin-5-yl]-7-oxabicyclo[2.2.1.]heptane-2- carboxamide  63(1R,2S,3S,4R,5S)-N-(3,4- >50 (9) dichlorophenyl)-5-methoxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  64(1R,2S,3S,4R,5R)-N-(3,4- 21 (253) dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  65(1R,2S,3S,4R,5R)-N-(3,4- 18 (169) dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1.]heptane-2- carboxamide  66(1S,2S,4R,5R,6R,7S)-N-(4- 20 (179) chloro-3-cyanophenyl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 67 (1S,2S,4R,5R,6R,7S)-N-(4- >50 (39) chloro-2-cyanophenyl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 68 (1S,2S,4R,5R,6R,7S)-N-(4- 15 (306) chloro-3-fluorophenyl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 69 (1S,2S,4R,5R,6R,7S)-7-(2- 21 (180) >20 (63)methylpyridin-4-yl)-N-[3- (trifluoromethoxy)phenyl]-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  70(1S,2S,4R,5R,6R,7S)-N-(5- >50 (25) >20 (1)methyl-1,3-thiazol-2-yl)-7-(2- methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  71(1S,2S,4R,5R,6R,7S)-N-[3- 6.2 (250) fluoro-4-(trifluoromethoxy)phenyl]-7-(2- methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  72(1S,2S,4R,5R,6R,7S)-N-(5,6- 7.7 (208) dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 73 (1R,2R,4S,5S,6S,7R)-N-(5,6- 16 (127) dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 74 (1S,2S,4R,5R,6R,7S)-N-(5,6- 7.7 (90) >20 (83)dichloropyridin-3-yl)-7-(6- methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  75(1S,2S,4R,5R,6R,7S)-N-(5,6- 4.4 (73) >20 (45) dichloropyridin-3-yl)-7-(pyrimidin-5-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide  76(1S,2S,4R,5R,6R,7S)-N-(5,6- 5.8 (123) dichloropyridin-3-yl)-7-(2-methoxypyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 77 rac-(1R,2R,3S,4R,5S)-N-(3,4- dichlorophenyl)-5-hydroxy-3-(2- 26 (49)methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  77a(1R,2R,3S,4R,5S)-N-(3,4- 26 (182) 0.69 (120) 3.5 (114) >20 (45)dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  77b (1S,2R,3S,4S,6R)-N-(3,4- 20(157) >20 (47) dichlorophenyl)-6-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  77c (1S,2S,3R,4S,5R)-N-(3,4- 13(72) 3.9 (72) dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  77d (1R,2S,3R,4R,6S)-N-(3,4- 33(92) >20 (54) dichlorophenyl)-6-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  78(1R,2R,3S,4R,5S)-N-[3-chloro-4- >50 (70) (2-fluorophenyl)phenyl]-5-hydroxy-3-(2-methylpyridin-4-yl)- 7-oxabicyclo[2.2.1]heptane-2-carboxamide  79 (1R,2R,3S,4R,5S)-5-hydroxy-N- >50 (113) >20 (34)(1-methanesulfonylpiperidin-4- yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  80 (1R,2R,3S,4R,5S)-N-(4,5- >50(32) dichloropyridin-2-yl)-5-hydroxy- 3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  81(1R,2R,3S,4R,5S)-N-(5-chloro- 2.7 (34) 6-methylpyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  82(1R,2R,3S,4R,5S)-N-(3,4- >50 (74) dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  83(1R,2R,3S,4R,5S)-N-(5,6- >50 (38) 1.5 (150) 12 (106) >20 (34)dichloropyridin-3-yl)-5-hydroxy- 3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  84 (1S,2S,3R,4S,5R)-N-(5,6- >50(61) >20 (31) dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  85(1R,2R,3S,4R,5S)-5-hydroxy-3- >50 (56) (2-methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  86(1S,2R,3S,4S,6R)-6-hydroxy-3- >50 (38) (2-methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  87(1R,2R,3S,4R,5S)-N-(5,6- >50 (14) dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  88(1R,2R,3S,4R,5S)-5-hydroxy-3- >50 (27) (pyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  89(1S,2R,3S,4S,6R)-6-hydroxy-3- >50 (0) (pyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  90rac-(1R,2R,3S,4R,5S)-N-(5,6- >50 (45) dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1]heptane-2- carboxamide 90a (1R,2R,3S,4R,5S)-N-(5,6- >50 (101) 2.3 (65) >50 (98) >20 (48)dichloropyridin-3-yl)-3-(2- fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2- carboxamide  90b(1S,2S,3R,4S,5R)-N-(5,6- >50 (44) >20 (45) dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1]heptane-2- carboxamide 91 (1R,2R,3S,4R,5S)-N-(5,6- 4.4 (66) dichloropyridin-3-yl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1]heptane-2-carboxamide  92 (1R,2R,3S,4R,5R)-N-(3,4- >50 (57)dichlorophenyl)-5-fluoro-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  93 (1S,2R,3S,4S,6S)-N-(3,4- >50(7) dichlorophenyl)-6-fluoro-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  94 (1S,2S,3R,4S,5S)-N-(3,4- 18(157) >20 (0) dichlorophenyl)-5-fluoro-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  95 (1R,2S,3R,4R,6R)-N-(3,4- 11(113) dichlorophenyl)-6-fluoro-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide  96(1R,2R,3S,4R,5R)-5-fluoro-3-(2- 14 (281) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide  97(1R,2R,3S,4R,5R)-5-fluoro-N-(6- >50 (2) methoxypyridin-3-yl)-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  98(1R,2R,3S,4R,5R)-N-(5,6- 21 (404) dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide  99(1R,2R,3S,4R,5R)-5-fluoro-3-(2- 18 (383) methylpyridin-4-yl)-N-[3-(trifluoromethoxy)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 100(1R,2R,3S,4R,5R)-5-fluoro-N-[3- 18 (310) fluoro-4-(trifluoromethoxy)phenyl]-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 101(1R,2R,3S,4R,5R)-5-fluoro-N-(1- 29 (62) methyl-1H-pyrazol-3-yl)-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 102(1R,2R,3S,4R,5R)-5-fluoro-N-(5- 2.1 (84) methyl-1,3-thiazol-2-yl)-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 103(1R,2R,3S,4R,5S)-N-(3,4- 24 (153) 10 (79) dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 104(1S,2R,3S,4S,6R)-N-(3,4- 14 (96) dichlorophenyl)-6-fluoro-3-(2-methoxypyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 105(1R,2R,3S,4R,5S)-N-(3,4- 8.2 (106) 1.7 (68)dichlorophenyl)-5-fluoro-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 106 (1S,2R,3S,4S,6R)-N-(3,4- 24(84) dichlorophenyl)-6-fluoro-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 107(1R,2R,3S,4R,5S)-5-fluoro-3-(2- 12 (139) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 108(1S,2R,3S,4S,6R)-6-fluoro-3-(2- 27 (137) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 109(1R,2R,3S,4R,5S)-N-(5,6- 28 (164) dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 110(1S,2R,3S,4S,6R)-N-(5,6- 28 (199) dichloropyridin-3-yl)-6-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 111(1R,2R,3S,4R,5S)-N-(3,4- 28 (87) dichlorophenyl)-5-fluoro-3-(2-fluoropyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 112(1S,2R,3S,4S,6R)-N-(3,4- 28 (99) dichlorophenyl)-6-fluoro-3-(2-fluoropyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 113(1R,2R,3S,4R,5S)-3-(2- 30 (103) aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-fluoro-7- oxabicyclo[2.2.1]heptane-2- carboxamide 114(1S,2R,3S,4S,6R)-3-(2- 30 (127) aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-6-fluoro-7- oxabicyclo[2.2.1]heptane-2- carboxamide 115(1R,2R,3S,4R,5S)-N-(3,4- 33 (49) dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 116(1S,2R,3S,4S,6R)-N-(3,4- 23 (58) dichlorophenyl)-6-fluoro-3-(6-methylpyridin-3-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 117(1S,2S,4R,5R,6R,7S)-N-(3,4- 3.0 (177) 7.0 (59) dichlorophenyl)-7-(2-methylpyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide118 (1S,2S,4R,5R,6R,7S)-N-(3,4- 8.2 (118) dichlorophenyl)-7-(2-methoxypyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide119 (1S,2S,4R,5R,6R,7S)-N-(3,4- 25 (149) dichlorophenyl)-7-(2-fluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide120 (1S,2S,4R,5R,6R,7S)-N-(3,4- 20 (102) 4.4 (119) dichlorophenyl)-7-[6-(trifluoromethyhpyridin-2-yl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide 121 rac-(1S,2S,4R,5R,6R,7S)-7-(2- 26 (353)methylpyridin-4-yl)-N-[3- (trifluoromethyl)phenyl]-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 121a(1S,2S,4R,5R,6R,7S)-7-(2- 2.7 (231) 4.5 (80) methylpyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide 121b (1R,2R,4S,5S,6S,7R)-7-(2- 22 (92)methylpyridin-4-yl)-N-[3- (trifluoromethyl)phenyl]-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 122rac-(1S,2S,4R,5R,6R,7S)-N-(3,4- 5.0 (32) dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide122a (1S,2S,4R,5R,6R,7S)-N-(3,4- 25 (160) dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide122b (1R,2R,4S,5S,6S,7R)-N-(3,4- 17 (217) dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide123 (1S,2S,4R,5R,6R,7S)-N-(6- >50 (0) >20 (48)methoxypyridin-3-yl)-7-(6- methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 124(1S,2S,4R,5R,6R,7S)-N-(5,6- 2.8 (160) 17(59)dichloropyridin-3-yl)-7-(2,3- difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 125(1S,2S,4R,5R,6R,7S)-N-(6- 17 (162) methoxypyridin-3-yl)-7-(pyridin-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 126rac-(1S,2S,4R,5R,6R,7S)-N-(3,4- 10 (212) dichlorophenyl)-7-(pyrimidin-5-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 126a(1S,2S,4R,5R,6R,7S)-N-(3,4- 5.4 (233) dichlorophenyl)-7-(pyrimidin-5-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 126b(1R,2R,4S,5S,6S,7R)-N-(3,4- 5.6 (103) >20 (42)dichlorophenyl)-7-(pyrimidin-5- yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 127(1S,2S,4R,5R,6R,7S)-7-(2,3- >50 (62) difluoropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide128 (1S,2S,4R,5R,6R,7S)-N-(6- >50 (27) >20 (39)methoxypyridin-3-yl)-7-[6- (trifluoromethyl)pyridin-2-yl]-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 129(1S,2S,4R,5R,6R,7S)-N-(3,4- 10 (146) dichlorophenyl)-7-(2-fluoropyrimidin-5-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide130 (1S,2S,4R,5R,6R,7S)-7- 10 (237) (pyrimidin-5-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide 131 (1S,2S,4R,5R,6R,7S)-7- 19 (360) (pyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide 132 (1S,2S,4R,5R,6R,7S)-7-(2- 18 (321)aminopyrimidin-5-yl)-N-(3,4- dichlorophenyl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 133(1S,2S,4R,5R,6R,7S)-N-(3,4- 25 (158) dichlorophenyl)-7-[2-(morpholin-4-yl)pyrimidin-5-yl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide134 (1S,2S,4R,5R,6R,7S)-7-(2- 19 (249) fluoropyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-8- oxatricyclo[3.2.1.0^(2,4)]octane-6-carboxamide 135 (1S,2S,4R,5R,6R,7S)-N-(3,4- 16 (237)dichlorophenyl)-7-(2- methylpyrimidin-5-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 136(1S,2S,4R,5R,6R,7S)-N-(5,6- 17 (254) dichloropyridin-3-yl)-7-(pyridin-4-yl)-8- oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 137(1S,2S,4R,5R,6R,7S)-N-(3,4- 21 (202) dichlorophenyl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0^(2,4)]octane-6- carboxamide 138(1R,2R,3S,4R,5S)-N-(3,4- >50 (0) >20 (24)dichlorophenyl)-5-hydroxy-3-(6- methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 139 rac-(1R,2R,3S,4R,5S)-N-(3,4-21 (223) dichlorophenyl)-5-hydroxy-3-(2- methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 139a (1R,2R,3S,4R,5S)-N-(3,4- 25(275) 1.8 (54) dichlorophenyl)-5-hydroxy-3-(2- methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 139b (1S,2S,3R,4S,5R)-N-(3,4- 26(141) 7.7 (82) dichlorophenyl)-5-hydroxy-3-(2- methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 140 (1R,2R,3S,4R,5S)-N-(3,4- 15(292) dichlorophenyl)-5-hydroxy-3-[6- (trifluoromethyl)pyridin-2-yl]-7-oxabicyclo[2.2.1]heptane-2- carboxamide 141 (1R,2R,3S,4R,5S)-N-(3,4- 13(43) dichlorophenyl)-5-hydroxy-3- (pyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 142 rac-(1R,2R,3S,4R,5S)-N-(3,4-28 (142) dichlorophenyl)-3-(2- fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2- carboxamide 142a (1R,2R,3S,4R,5S)-N-(3,4- 22(68) 1.2 (83) 33 (93) 6.6 (81) dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1]heptane-2- carboxamide142b (1S,2S,3R,4S,5R)-N-(3,4- 0.79 (54) dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7- oxabicyclo[2.2.1]heptane-2- carboxamide143 (1R,2R,3S,4R,5S)-3-(2- >50 (0) aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7- oxabicyclo[2.2.1]heptane-2- carboxamide 144(1R,2R,3S,4R,5S)-N-(3,4- 30 (183) dichlorophenyl)-3-[2-(dimethylamino)pyrimidin-5-yl]-5- hydroxy-7- oxabicyclo[2.2.1]heptane-2-carboxamide 145 (1R,2R,3S,4R,5S)-N-(3,4- 17 (246)dichlorophenyl)-5-hydroxy-3-[2- (trifluoromethyl)pyridin-4-yl]-7-oxabicyclo[2.2.1]heptane-2- carboxamide 145a (1R,2R,3S,4R,5S)-N-(3,4-1.2 (100) dichlorophenyl)-5-hydroxy-3-[2-(trifluoromethyl)pyridin-4-yl]-7- oxabicyclo[2.2.1]heptane-2-carboxamide 145b (1S,2S,3R,4S,5R)-N-(3,4- 11 (83)dichlorophenyl)-5-hydroxy-3-(2- (trifluoromethyhpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 146 (1R,2R,3S,4R,5S)-N-(3,4- 20(150) dichlorophenyl)-3-(2,3- difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2- carboxamide 147 (1R,2R,3S,4R,5S)-N-(3,4- 28(284) dichlorophenyl)-3-(2,5- difluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2- carboxamide 148 (1R,2R,3S,4R,5S)-N-(3,4- 7.8(51) 18 (58) dichlorophenyl)-5-hydroxy-3-(2- methylpyrimidin-5-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 149 (1R,2R,3S,4R,5S)-3-(2- 26(112) 8.3 (58) aminopyridin-4-yl)-N-(3,4- dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2- carboxamide (150 1R,2R,3S,4R,5S)-N-(3,4- >50(5) dichlorophenyl)-5-hydroxy-3- (pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 151 (1R,2R,3S,4R,5S)-N-(3,4- >50(0) dichlorophenyl)-3-(2- fluoropyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2- carboxamide 152 (1R,2R,3S,4R,5S)-N-(3,4-12 (44) 2.0 (61) dichlorophenyl)-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 153(1R,2R,3S,4R,5S)-N-(3,4- 19 (121) >20 (46)dichlorophenyl)-5-hydroxy-3-(1- methyl-1H-pyrazol-3-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 154 (1R,2R,3S,4R,5S)-N-(3,4- 26(236) 4.0 (75) dichlorophenyl)-5-hydroxy-3-[2-(trifluoromethyl)pyrimidin-5-yl]-7- oxabicyclo[2.2.1]heptane-2-carboxamide 155 (1R,2R,3S,4R,5S)-N-(3,4- 26 (262)dichlorophenyl)-5-methoxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 156 (1S,2R,3S,4R,5S,6R)-N-(3,4-18 (28) 0.95 (99) 15 (103) >20 (42) dichlorophenyl)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 157(1R,2S,3R,4S,5R,6S)-N-(3,4- 29 (57) 2.1 (59) 32 (84) >20 (15)dichlorophenyl)-5,6-dihydroxy-3- (2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 158 (1S,2R,3S,4R,5S,6R)-5,6- >50(31) dihydroxy-3-(2-methylpyridin-4- yl)-N-[3-(trifluoromethyl)phenyl]-7-oxabicyclo[2.2.1]heptane-2- carboxamide 159(1S,2R,3S,4R,5S,6R)-5,6- >50 (11) dihydroxy-3-(pyridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 160(1S,2R,3S,4R,5S,6R)-N-(3,4- >50 (32) dichlorophenyl)-5,6-dihydroxy-3-(pyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 161(1S,2R,3S,4R,5S,6R)-5,6- >50 (29) dihydroxy-3-(2-methylpyridin-4-yl)-N-[2-(trifluoromethyhpyridin- 4-yl]-7-oxabicyclo[2.2.1]heptane-2-carboxamide 162 (1S,2R,3S,4R,5S,6R)-N-(5,6- >50 (25)dichloropyridin-3-yl)-5,6- dihydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 163(1S,2R,3S,4R,5S,6R)-5,6- >50 (23) dihydroxy-N-[6-methyl-5-(trifluoromethyl)pyridin-3-yl]-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 164 (1R,2R,3S,4R,5R)-N-(3,4- >50(0) dichlorophenyl)-5-fluoro-3-(6- methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 165 (1R,2R,3S,4R,5R)-N-(3,4- 6.0(110) >20 (59) dichlorophenyl)-5-fluoro-3-(2- methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 166 (1R,2R,3S,4R,5R)-N-(3,4- 24(68) >20 (0) dichlorophenyl)-5- (dimethylamino)-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 167(1R,2R,3S,4R,5R)-N-(3,4- 6.9 (83) dichlorophenyl)-5- (methylamino)-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2- carboxamide 168(1R,2R,3S,4R,5R)-N-(3,4- 0.32 (114) >20 (0) dichlorophenyl)-5-[(2-hydroxyethyl)amino]-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 169 (1R,2R,3S,4R,5R)-N-(3,4- >50(69) >20 (54) dichlorophenyl)-3-(2- methylpyridin-4-yl)-5-[(oxan-4-yl)amino]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 170(1R,2R,3S,4R,5R)-N-(3,4- >50 (37) dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-{[(1r,3r)-3- hydroxycyclobutyl]amino}-7-oxabicyclo[2.2.1]heptane-2- carboxamide 171 (1R,2R,3S,4R,5R)-N-(3,4- 24(237) dichlorophenyl)-3-(2- fluoropyridin-4-yl)-5- (methylamino)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 172 (1R,2R,3S,4R,5R)-N-(3,4- 16(177) dichlorophenyl)-5- (dimethylamino)-3-(2- fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 173 (1R,2R,3S,4R,5R)-N-(3,4- 27(54) dichlorophenyl)-3-(2- fluoropyridin-4-yl)-5-[(2-hydroxyethyl)amino]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 174(1R,2R,3S,4R,5R)-N-(5,6- >50 (37) dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5- (methylamino)-7- oxabicyclo[2.2.1]heptane-2-carboxamide 175 (1R,2R,3S,4R,5R)-N-(5,6- 29 (186)dichloropyridin-3-yl)-5- (dimethylamino)-3-(2- fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 176 (1R,2R,3S,4R,5R)-N-(5,6- 25(51) dichloropyridin-3-yl)-3-(2- fluoropyridin-4-yl)-5-[(2-hydroxyethyl)amino]-7- oxabicyclo[2.2.1]heptane-2- carboxamide 177(1R,2R,3S,4R,5R)-N-(3,4- 22 (211) 1.5 (34) >50 (33) 1.5 (103)dichlorophenyl)-3-(2- methylpyridin-4-yl)-5-(morpholin-4-yl)-7-oxabicyclo[2.2.1]heptane- 2-carboxamide 178 (1R,2R,3S,4R,5R)-N-(3,4- >50 (1) dichlorophenyl)-5-hydroxy-5-methyl-3-(2-methylpyridin-4-yl)- 7-oxabicyclo[2.2.1]heptane-2-carboxamide 179 (1S,2S,3R,4S,5S)-N-(3,4- >50 (22)dichlorophenyl)-5-hydroxy-5- methyl-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 180 (1R,2R,3S,4R,5R)-N-(3,4-30 (113) 11 (69) dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide 181 (1S,2S,3R,4S,5S)-N-(3,4- 27(243) >20 (28) dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2- carboxamide

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula I, or a pharmaceutically acceptable salt, orstereoisomer thereof;

wherein R⁰ is hydrogen or C₁₋₆alkyl; R² is phenyl; a 5- or 6-memberedheteroaryl or a 5- or 6-membered heterocyclyl, each having 1 to 3heteroatoms selected from N, O and S; wherein R² is unsubstituted orsubstituted by 1 to 3 substituents independently selected from halo,C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆ alkoxy, halo-substitutedC₁₋₆alkoxy, cyano, C₁₋₆alkylsulfonyl, phenyl unsubstituted orsubstituted by halo or C₁₋₆ alkyl; R³ is a 5- or 6-membered heteroarylhaving 1 to 2 heteroatoms selected from N, O and S; wherein R³ isunsubstituted or substituted by 1 to 3 substituents independentlyselected from halo, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy or—NR⁵R⁶; R^(1a), R^(1b), R^(4a), and R^(4b) are each independentlyhydrogen, halo, hydroxyl, C₁₋₆alkoxy, —NR⁷R⁸ or —NR⁷—(CR⁹R¹⁰)₂₋₄—OR¹¹;or wherein one of R^(1a) and R^(1b) together with one of R^(4a) andR^(4b) form a cyclopropyl with the two carbon atoms to which saidR^(1a), R^(1b), R^(4a) and R^(4b) are respectively attached; providedthat R^(1a), R^(1b), R^(4a), and R^(4b) cannot all be hydrogen; R⁵, R⁶,R⁷, R⁹, R¹⁰ and R¹¹ are each independently hydrogen or C₁₋₆alkyl; R⁸ ishydrogen, C₃₋₇ cycloalkyl or a 5- or 6-membered heterocyclyl having 1-3heteroatoms selected from N, O and S; wherein said C₃₋₇ cycloalkyl or 5-or 6-membered heterocyclyl of R⁸ is unsubstituted or substituted byhydroxy or C₁₋₆ alkyl; alternatively, R⁵ and R⁶ or R⁷ and R⁸ togetherwith the nitrogen atom to which they are attached in —NR⁵R⁶ or —NR⁷R⁸respectively form a 5- or 6-membered heterocyclyl having 1-3 heteroatomsselected from N, O and S.
 2. The compound of claim 1, or apharmaceutically acceptable salt, or stereoisomer thereof, wherein saidcompound is of Formula (1A), (1B), (1C), (1D), (1E), (1F), (1G), (1H),(1I), (1J), (1K), (1L), (2A), (2B), (2C), (2D), (2E), (2F), (2G), (2H),(2I), (2J), (2K) or (2L);


3. The compound of claim 1, wherein one of R^(1a) and R^(1b) is hydrogenand the other is hydroxyl, fluoro, methoxy, methylamino,(2-hydroxyethyl)amino, di-methylamino, morpholin-4-yl, methyl,((tetrahydro-2H-pyran-4-yl)amino) or (3-hydroxycyclobutyl)amino.
 4. Thecompound of claim 1, wherein R^(1a) and R^(1b) are hydrogen, and one ofR^(4a) and R^(4b) is hydrogen and the other is hydroxyl or fluoro. 5.The compound of claim 1, wherein one of R^(1a) and R^(1b) and one ofR^(4a) and R^(4b) together with the carbon ring atoms form a cyclopropylfused to the bicyclic ring.
 6. The compound of claim 1, wherein R² isphenyl, pyridyl, pyrazolyl, thiazolyl or piperidinyl, each of which isunsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted C₁₋₆alkoxy, cyano, C₁₋₆ alkylsulfonyl, phenylunsubstituted or substituted by halo.
 7. The compound of claim 6,wherein R² is selected from: phenyl substituted by 3,4-dichloro;2-trifluoromethyl; 3-trifluoromethyl; 3-cyano-4-chloro;2-cyano-4-chloro; 3-fluoro-4-chloro; 3-trifluoromethoxy;3-fluoro-4-trifluoromethoxy; or 3-chloro-4-(2-fluorophenyl);pyridin-4-yl substituted by 6-methoxy or 2-trifluoromethyl; pyridin-3-ylsubstituted by 5,6-dichloro; 6-methoxy; 5-chloro-6-methyl or5-trifluoromethyl-6-methyl; pyridin-2-yl substituted by 4,5-dichloro;1H-pyrazol-3-yl substituted 1-methyl; thiazol-2-yl substituted by5-methyl; and piperidin-4-yl substituted by 1-methylsulfonyl.
 8. Thecompound of claim 1, wherein R³ is pyridyl, pyrimidinyl or pyrazolyl,each of which is unsubstituted or substituted by 1 to 2 substituentsindependently selected from halo, C₁₋₆alkyl, halo-substituted C₁₋₆alkyl,C₁₋₆alkoxy or —NR⁵R⁶.
 9. The compound of claim 8, wherein R³ is selectedfrom: pyridin-4-yl unsubstituted or substituted by 2-methyl;2-trifluoromethyl; 2-methoxy; 2-amino; 2-fluoro; 2,3-difluoro; or2,5-difluoro; pyridin-3-yl unsubstituted or substituted by 6-methyl;6-methoxy; or 5,6-dichloro; pyridin-2-yl substituted by6-trifluoromethyl; pyrimidin-5-yl unsubstituted or substituted by2-fluoro, 2-methyl, 2-amino, 2-trifluoromethyl, 2-morpholinyl or2-di-methylamino; pyrimidin-4-yl substituted by 2-methyl; and1H-pyrazol-4-yl or 1H-pyrazolyl-3-yl substituted by 1-methyl.
 10. Thecompound of claim 1, or a pharmaceutically acceptable salt, orstereoisomer thereof, wherein said compound is of Formula (2A) orFormula (2G);

wherein R is hydroxyl; R² is phenyl; a 5- or 6-membered heteroaryl or a5- or 6-membered heterocyclyl, each having 1 to 3 heteroatoms selectedfrom N, O and S; wherein R² is unsubstituted or substituted by 1 to 3substituents independently selected from halo, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆alkoxy,cyano, C₁₋₆alkylsulfonyl, phenyl unsubstituted or substituted by halo;R³ is a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms selectedfrom N, O and S; wherein R³ is unsubstituted or substituted by 1 to 3substituents independently selected from halo, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy or —NR⁵R⁶; R⁵ and R⁶ areindependently hydrogen or C₁₋₆alkyl; alternatively, R⁵ and R⁶ togetherwith the nitrogen atom to which they are form a 5- or 6-memberedheterocyclyl having 1-3 heteroatoms selected from N, O and S.
 11. Thecompound of claim 10, wherein R² is phenyl, pyridyl, pyrazolyl,thiazolyl or piperidinyl, each of which is unsubstituted or substitutedby 1 to 2 substituents independently selected from halo, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-substituted C₁₋₆alkoxy,cyano, C₁₋₆alkylsulfonyl, phenyl unsubstituted or substituted by halo.12. The compound of claim 10, wherein R² is selected from: phenylsubstituted by 3,4-dichloro; 2-trifluoromethyl; 3-trifluoromethyl;3-cyano-4-chloro; 2-cyano-4-chloro; 3-fluoro-4-chloro;3-trifluoromethoxy; 3-fluoro-4-trifluoromethoxy; or3-chloro-4-(2-fluorophenyl); pyridin-4-yl substituted by 6-methoxy or2-trifluoromethyl; pyridin-3-yl substituted by 5,6-dichloro; 6-methoxy;5-chloro-6-methyl or 5-trifluoromethyl-6-methyl; pyridin-2-ylsubstituted by 4,5-dichloro; 1H-pyrazol-3-yl substituted 1-methyl;thiazol-2-yl substituted by 5-methyl; and piperidin-4-yl substituted by1-methylsulfonyl.
 13. The compound of claim 10, wherein R³ is pyridyl,pyrimidinyl or pyrazolyl, each of which is unsubstituted or substitutedby 1 to 2 substituents independently selected from halo, C₁₋₆alkyl,halo-substituted C₁₋₆alkyl, C₁₋₆alkoxy or —NR⁵R⁶.
 14. The compound ofclaim 10, wherein R³ is pyridyl unsubstituted or substituted by 1 to 2substituents independently selected from fluoro, trifluoromethyl, methyland methoxy.
 15. A compound or a pharmaceutically acceptable salt orenantiomer thereof, wherein the compound is selected from compounds1-181 in Table
 2. 16. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt orstereoisomer thereof, and one or more pharmaceutically acceptablecarriers.
 17. A combination comprising a compound according to claim 1,or a pharmaceutically acceptable salt or stereoisomer thereof, and oneor more therapeutically active agents.
 18. A method for treating,ameliorating or preventing arthritis or joint injury, or for cartilagerepair in a mammal in need thereof, comprising administering atherapeutically effective amount of a compound according to claim 1, andoptionally in combination with a second therapeutic agent; therebytreating, ameliorating or preventing arthritis or joint injury, orrepairing cartilage, in said mammal.
 19. The method of claim 18, whereinsaid wherein said second therapeutic agent is selected fromangiopoietin-like 3 protein (ANGPTL3), insulin growth factor (IGF1),SM04690, Janus kinase inhibitor, oral salmon calcitonin, SD-6010,vitamin D3, collagen hydrolyzate, bone morphogenetic protein 7 (BMP7),rusalatide acetate, avocado soy unsaponifiables (ASU), a steroid, anon-steroidal anti-inflammatory agent (NSAID), hyaluronic acid,kartogenin, TPX-100, and a compound having Formula (II);

or a pharmaceutically acceptable salt, or a stereoisomer thereof,wherein R¹ is phenyl or 5- or 6-membered heteroaryl; and R¹ isunsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, cyano, C₁₋₆alkyl, C₁₋₄haloalkyl, —C(O)R¹³,—C(O)OR¹³, —NR^(14a)R^(14b), 5- and 6-membered heterocyclyl, phenyl, and5- and 6-membered heteroaryl; wherein R¹³ is C₁₋₆alkyl or amino; R^(14a)and R^(14b) are independently is selected from hydrogen, C₁₋₆alkyl,—C(O)R¹⁵, and —C(O)OR¹⁵; and R¹⁵ is C₁₋₄alkyl; and wherein saidheterocyclyl, phenyl, or heteroaryl substituent of R¹ is unsubstitutedor substituted by 1 to 2 substituents independently selected from halo,hydroxy, and C₁₋₆alkyl; R³ is phenyl or 5- or 6-membered heteroaryl; andR³ is unsubstituted or substituted by 1 to 2 substituents independentlyselected from halo, cyano, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, —C(O)R¹⁶, —C(O)OR¹⁶, 5- and 6-membered heterocyclyl, andphenyl; wherein R¹⁶ is C₁₋₆alkyl; and said heterocyclyl or phenyl of R³is unsubstituted or substituted by 1 to 2 substituents selected fromhalo and cyano; R² and R⁴ are independently hydrogen or C₁₋₆alkyl; or R²and R⁴ taken together form a cyclopropyl fused to the bicyclic ring, orR² and R⁴ taken together form a bond, producing a double bond betweenthe two carbons to which R² and R⁴ are attached.
 20. The method of claim19, wherein said compound having Formula (II) is selected from:(1R,2S,3R,4S)—N-(3,4-dichlorophenyl)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2R,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;(1S,2S,3R,4R)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(1R,2S,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamideN-(2-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-3-(1H-pyrazol-5-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(1S,2S,3R,4R)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(1R,2R,3S,4S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide(1R,2R,4S,5S)—N-(3,4-dichlorophenyl)-4-(pyridin-4-yl)-8-oxatricyclo[3.2.1.02,4]octane-2-carboxamide(1R,2R,3S,4S)—N-(3,4-dichlorophenyl)-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide;andN-(2,2′-difluoro-[1,1′-biphenyl]-4-yl)-3-(pyrazin-2-yl)-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxamide.